6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection

ABSTRACT

The invention provides novel compounds having the general formula: 
                         
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, W and n are as described herein, compositions including the compounds and methods of using the compounds.

This application is a continuation of U.S. application Ser. No.14/946,595, filed Nov. 19, 2015, (now U.S. Pat. No. 10,081,627), whichis a continuation of U.S. application Ser. No. 14/640,397 (now U.S. Pat.No. 9,233,978), filed Mar. 6, 2015 which claims the benefit of priorityto International Application No. PCT/CN2014/073068, filed Mar. 7, 2014,International Application No. PCT/CN2014/083027, filed Jul. 25, 2014,and International Application No. PCT/CN2015/070895, filed Jan. 16,2015, each of which is incorporated herein by reference in its entirety.

The present invention relates to organic compounds useful for therapyand/or prophylaxis in a human, and in particular to Hepatitis B virus(HBV) inhibitors by targeting on HBV capsid for the treatment of HBVinfection.

FIELD OF THE INVENTION

The present invention relates to novel 6-fusedheteroaryldihydropyrimidines having pharmaceutical activity, theirmanufacture, pharmaceutical compositions containing them and theirpotential use as medicaments.

The present invention relates to compounds of formula (I)

wherein R¹ to R⁶, X, Y, W and n are as described below, or topharmaceutically acceptable salts, or to enantiomers or diastereomersthereof.

HBV is a species of the hepadnaviridae family of viruses. HBV is aserious public health problem worldwide, with more than 400 millionpeople especially in Asia-pacific regions chronically infected by thissmall enveloped DNA virus. Although most individuals seem to resolve theinfection following acute symptoms, 15-40% of HBV patients will finallydevelop clinical diseases during their lifespan, most notably,hepatitis, liver cirrhosis, and hepatocellular carcinoma. Every year500,000 to 1 million people die from the end stage of liver diseasescaused by HBV infection.

HBV lifecycle begins with the binding of the “Dane” particle with anunidentified receptor on the surface of hepatocyte. Following entry,viral genome is delivered into nucleus where a covalently closedcircular DNA (cccDNA) is formed through DNA repair of viral relaxedcircular DNA. Unlike the mechanisms of most other DNA viruses, HBVcccDNA replicates through the retrotranscription of a 1.1-genomeunit-length RNA copy (pregenomic RNA). Viral pregenomic RNA interactswith other two viral components, capsid protein and polymerase, as wellas some host factors, to form capsid particles where viral DNAreplication occurs. Most copies of the encapsidated genome thenefficiently associate with the envelope proteins for virion assembly andsecretion; a minority of these genomes is shunted to the nucleus, wherethey are converted to cccDNA.

Currently, there are two types of anti-HBV agents on the market,nucleoside (tide) analogs targeting viral polymerase (lamivudine,adefovir, tenofovir, telbivudine and entecavir) and interferonmodulating host immune functions. Mutations in the primary sequence ofthe polymerase that confer resistance to lamivudine and adefovir havebeen identified clinically and underlie a rebound of serum virus titersthat 70% of treated patients experience within 3 years of the start oflamivudine therapy. Although resistance to telbivudine, adefovir, andentecavir occurs more rarely, it has been recorded. Interferon alpha isthe other major therapy available for hepatitis B, but it is limited bya poor long-term response and debilitating side effects. Some viralgenotypes do not show good responses to interferon therapy. Now, thestandard of clinic cure of HBV infection is the loss and/orseroconversion of HBsAg. The majority (around or more than 90%) oftreated patients fail to achieve this goal. This drawback is mainly dueto the presence of a stable pool of viral cccDNA in nucleus that doesn'treplicate itself, therefore, shows no accessibility to nucleoside (tide)analogs.

Hence, there is certainly a medical need for treatments with improvedcharacteristics and for a diversity of approaches in the development oftherapies for HBV infection.

HBV capsid protein plays essential roles in HBV replication. HBV has anicosahedral core comprising of 240 copies of the capsid (or core)protein. The predominant biological function of capsid protein is to actas a structural protein to encapsidate pre-genomic RNA and form immaturecapsid particles in the cytoplasm. This step is prerequisite for viralDNA replication. The HBV capsid spontaneously self-assembles from manycopies of core dimers present in the cytoplasm. It has been shown thatthe formation of a trimeric nucleus and the subsequent elongationreactions occur by adding one dimeric subunit at a time until it iscomplete. Besides this function, capsid protein regulates viral DNAsynthesis through different phosphorylation status of its C-terminalphosphorylation sites. When a near full-length relaxed circular DNA isformed through reverse-transcription of viral pregenomic RNA, animmature capsid becomes a mature capsid. On one hand, capsid proteinmight facilitate the nuclear translocation of viral relaxed circulargenome by means of the nuclear localization signals located in theArginine-rich domain of the C-terminal region of capsid protein. Innucleus, as a component of viral cccDNA minichromosome, capsid proteincould play a structural and regulatory role in the functionality ofcccDNA minichromosomes. Capsid protein also interacts with viral largeenvelope protein in endoplasmic reticulum and triggers the release ofintact viral particles from hepatocytes.

There has been a couple of capsid related anti-HBV inhibitors reported.For example, phenylpropenamide derivatives, including compounds namedAT-61 and AT-130 (Feld J. et al. Antiviral Research 2007, 168-177), anda class of thiazolidin-4-ones from Valeant R&D (WO2006/033995), havebeen shown to inhibit pgRNA packaging. A recent study suggested thatphenylpropenamides are, in fact, accelerators of HBV capsid assembly,and their actions result in the formation of empty capsids. These veryinteresting results illustrate the importance of the kinetic pathway insuccessful virus assembly.

Heteroaryldihydropyrimidines or HAP, including compounds named Bay41-4109, Bay 38-7690 and Bay 39-5493, were discovered in a tissueculture-based screening (Deres K. et al. Science 2003, 893). These HAPanalogs act as synthetic allosteric activators and are able to induceaberrant capsid formation that leads to degradation of the core protein.HAP analogs also reorganized core protein from preassembled capsids intononcapsid polymers, presumably by interaction of HAP with dimers freedduring capsid ‘breathing’, the transitory breaking of individualintersubunit bonds. Bay 41-4109 was administered to HBV infectedtransgenic mouse or humanized mouse models and demonstrated in vivoefficacy with HBV DNA reduction (Deres K. et al. Science 2003, 893;Brezillon N. et al. PLoS ONE 2011, e25096). It was also shown thatbis-ANS, a small molecule that acts as a molecular ‘wedge’ andinterferes with normal capsid-protein geometry and capsid formation(Zlotnick A. et al. J Virol. 2002, 4848-4854).

SUMMARY OF THE INVENTION

The present invention relates to novel compounds of formula (I)

wherein

wherein

-   R¹ is hydrogen, halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen, hydroxyC₁₋₆alkyl, aminocarbonyl, C₁₋₆alkoxycarbonyl    or carboxy;-   R⁶ is hydrogen, C₁₋₆alkoxycarbonyl or carboxy-C_(m)H_(2m)—;-   X is carbonyl or sulfonyl;-   Y is —CH₂—, —O— or —N(R⁷)—,    -   wherein R⁷ is hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl,        C₃₋₇cycloalkyl-C_(m)H_(2m)—, C₁₋₆alkoxycarbonyl-C_(m)H_(2m)—,        —C_(t)H_(2t)—COOH, -haloC₁₋₆alkyl-COOH,        —(C₁₋₆alkoxy)C₁₋₆alkyl-COOH, —C₁₋₆alkyl-O—C₁₋₆alkyl-COOH,        —C₃₋₇cycloalkyl-C_(m)H_(2m)—COOH,        —C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH, hydroxy-C_(t)H_(2t)—,        carboxyspiro[3.3]heptyl or carboxyphenyl-C_(m)H_(2m)—,        carboxypyridinyl-C_(m)H_(2m)—;-   W is —CH₂—, —C(C₁₋₆alkyl)₂-, —O— or carbonyl;-   n is 0 or 1;-   m is 0-7;-   t is 1-7;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

The invention is also relates to their manufacture, medicaments based ona compound in accordance with the invention and their production as wellas the use of compounds of formula (I) or other compounds of the presentinvention for the treatment or prophylaxis of HBV infection.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, the term “C₁₋₆alkyl” signifies a saturated, linear- orbranched chain alkyl group containing 1 to 6, particularly 1 to 4 carbonatoms, for example methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl,tert-butyl and the like. Particular “C₁₋₆alkyl” groups are methyl,ethyl, isopropyl and tert-butyl.

The term “—C_(m)H_(2m)—” alone or in combination signifies a saturated,linear or branched chain alkyl group containing m (m≠0) carbon atoms ora bond (m=0). In particular, “—C_(m)H_(2m)—” alone or in combinationsignifies a saturated, linear or branched chain alkyl group containing 1to 4 carbon atoms.

The term “—C_(t)H_(2t)—” alone or in combination signifies a chemicallink or a saturated, linear or branched chain alkyl group containing t(t≠0) carbon atoms or a bond (t=0). In particular, “—C_(t)H_(2t)—” aloneor in combination signifies a saturated, linear or branched chain alkylgroup containing 1 to 4 carbon atoms.

The term “C₁₋₆alkoxy” alone or in combination signifies a groupC₁₋₆alkyl-O—, wherein the “C₁₋₆alkyl” is as defined above; for examplemethoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, 2-butoxy,tert-butoxy and the like. Particular “C₁₋₆alkoxy” groups are methoxy andethoxy and more particularly methoxy.

The term “C₃₋₇cycloalkyl”, alone or in combination, refers to asaturated carbon ring containing from 3 to 7 carbon atoms, particularlyfrom 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and the like. Particular “C₃₋₇cycloalkyl” groups are cyclopropyl, cyclopentyl and cyclohexyl.

The term “carboxy” refers to the group —COOH.

The term “carbonyl” alone or in combination refers to the group —C(O)—.

The term “sulfonyl” alone or in combination refers to the group —S(O)₂—.

The term “halogen” and “halo” are used interchangeably herein and referto fluoro, chloro, bromo, or iodo.

The term “haloC₁₋₆alkyl” refers to an alkyl group wherein at least oneof the hydrogen atoms of the alkyl group has been replaced by same ordifferent halogen atoms, particularly fluoro atoms. Examples ofhaloC₁₋₆alkyl include monofluoro-, difluoro- or trifluoro-methyl, -ethylor -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl,2,2,2-trifluoroethyl, fluoromethyl, difluoroethyl or trifluoromethyl.

The term “C₁₋₆alkoxycarbonyl” refers to a group C₁₋₆alkoxy-C(O)—,wherein the “C₁₋₆alkoxy” is as defined above.

The term “carboxy-C_(m)H_(2m)—” refers to a group “—C_(m)H_(2m)—COOH”,wherein the “—C_(m)H_(2m)—” is as defined above.

The term “C₃₋₇cycloalkyl-C_(m)H_(2m)—” refers to a “C₃₋₇cycloalkyl”group as defined above wherein one of the hydrogen atoms of the“C₃₋₇cycloalkyl” group is replaced by a “—C_(m)H_(2m)—” group.

The term “enantiomer” denotes two stereoisomers of a compound which arenon-superimposable mirror images of one another.

The term “diastereomer” denotes a stereoisomer with two or more centersof chirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and activities.

The compounds according to the present invention may exist in the formof their pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” refers to conventional acid-addition salts orbase-addition salts that retain the biological effectiveness andproperties of the compounds of formula (I) or other compounds of thepresent invention and are formed from suitable non-toxic organic orinorganic acids or organic or inorganic bases. Acid-addition saltsinclude for example those derived from inorganic acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,sulfamic acid, phosphoric acid and nitric acid, and those derived fromorganic acids such as p-toluenesulfonic acid, salicylic acid,methanesulfonic acid, oxalic acid, succinic acid, citric acid, malicacid, lactic acid, fumaric acid, and the like. Base-addition saltsinclude those derived from ammonium, potassium, sodium and, quaternaryammonium hydroxides, such as for example, tetramethyl ammoniumhydroxide. The chemical modification of a pharmaceutical compound into asalt is a technique well known to pharmaceutical chemists in order toobtain improved physical and chemical stability, hygroscopicity,flowability and solubility of compounds. It is for example described inBastin R. J., et al., Organic Process Research & Development 2000, 4,427-435; or in Ansel, H., et al., In: Pharmaceutical Dosage Forms andDrug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Particularare the sodium salts of the compounds of formula (I).

Compounds of the general formula (I) or other compounds of the presentinvention which contain one or several chiral centers can either bepresent as racemates, diastereomeric mixtures, or optically activesingle isomers. The racemates can be separated according to knownmethods into the enantiomers. Particularly, diastereomeric salts whichcan be separated by crystallization are formed from the racemic mixturesby reaction with an optically active acid such as e.g. D- or L-tartaricacid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.

HBV Capsid Inhibitor

The present invention provides (i) novel compounds having the generalformula (I):

wherein

-   R¹ is hydrogen, halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen, hydroxyC₁₋₆alkyl, aminocarbonyl, C₁₋₆alkoxycarbonyl    or carboxy;-   R⁶ is hydrogen, C₁₋₆alkoxycarbonyl or carboxy-C_(m)H_(2m)—;-   X is carbonyl or sulfonyl;-   Y is —CH₂—, —O— or —N(R⁷)—,    -   wherein R⁷ is hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl,        C₃₋₇cycloalkyl-C_(m)H_(2m)—, C₁₋₆alkoxycarbonyl-C_(m)H_(2m)—,        —C_(t)H_(2t)—COOH, -haloC₁₋₆alkyl-COOH,        —(C₁₋₆alkoxy)C₁₋₆alkyl-COOH, —C₁₋₆alkyl-O—C₁₋₆alkyl-COOH,        —C₃₋₇cycloalkyl-C_(m)H_(2m)—COOH,        —C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH, hydroxy-C_(t)H_(2t)—,        carboxyspiro[3.3]heptyl or carboxyphenyl-C_(m)H_(2m)—,        carboxypyridinyl-C_(m)H_(2m)—;-   W is —CH₂—, —C(C₁₋₆alkyl)₂-, —O— or carbonyl;-   n is 0 or 1;-   m is 0-7;-   t is 1-7;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Another embodiment of present invention is (ii) a compound of formula I,wherein

-   R¹ is hydrogen, chloro, bromo or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen, chloro or fluoro;-   R⁴ is methyl, ethyl or propyl;-   R⁵ is hydrogen, hydroxymethyl, aminocarbonyl, methoxycarbonyl or    carboxy;-   R⁶ is hydrogen, methyl-O-carbonyl or carboxymethyl;-   X is carbonyl or sulfonyl;-   Y is —CH₂—, —O—, —N(R⁷)—,    -   wherein R⁷ is hydrogen, methyl, difluoroethyl, isopropyl,        isobutyl, t-butyl, cyclopropyl, cyclopropylmethyl,        methyl-O-carbonylisopropyl, carboxyethyl, carboxydifluoroethyl,        carboxypropyl, carboxybutyl, carboxy(gemdimethyl)methyl,        carboxy(gemdimethyl)ethyl, carboxy(gemdimethyl)propyl,        carboxy(gemdimethyl)butyl, carboxy(methyl)ethyl,        carboxy(ethyl)ethyl, carboxy(methoxy)ethyl, carboxycyclobutyl,        carboxycyclobutylmethyl, carboxycyclopentyl, carboxycyclohexyl,        carboxymethylcyclopropyl, carboxycyclopropylmethyl,        carboxycyclobutylmethyl, carboxyspiro[3.3]heptyl,        carboxymethoxyethyl, carboxymethoxypropyl, hydroxyethyl,        hydroxymethyl(gemdimethyl)butyl, hydroxy(gemdimethyl)ethyl,        carboxyphenyl, carboxypyridinyl or carboxyphenylmethyl;-   W is —CH₂—, —C(CH₃)₂—, —O— or carbonyl;-   n is 0 or 1;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Another embodiment of the present invention is (iii) a compound offormula (IA),

wherein

-   R¹ is halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen, hydroxyC₁₋₆alkyl, aminocarbonyl, C₁₋₆alkoxycarbonyl    or carboxy;-   R⁶ is hydrogen, C₁₋₆alkoxycarbonyl or carboxy-C_(m)H_(2m)—;-   Y is —N(R⁷)—,    -   wherein R⁷ is hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl,        C₃₋₇cycloalkyl-C_(m)H_(2m)—, C₁₋₆alkoxycarbonyl-C_(m)H_(2m)—,        —C_(t)H_(2t)—COOH, -haloC₁₋₆alkyl-COOH,        —(C₁₋₆alkoxy)C₁₋₆alkyl-COOH, —C₁₋₆alkyl-O—C₁₋₆alkyl-COOH,        —C₃₋₇cycloalkyl-C_(m)H_(2m)—COOH,        —C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH, hydroxy-C_(t)H_(2t)—,        carboxyspiro[3.3]heptyl or carboxyphenyl-C_(m)H_(2m)—,        carboxypyridinyl-C_(m)H_(2m)—;-   W is —CH₂— or carbonyl;-   m is 0-7;-   t is 1-7;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

A further embodiment of the present invention is (iv) a compound offormula (I) or (IA) or pharmaceutically acceptable salts, or enantiomersor diastereomers thereof, wherein

-   R¹ is chloro, bromo or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen, chloro or fluoro;-   R⁴ is methyl, ethyl or propyl;-   R⁵ is hydrogen, hydroxymethyl, aminocarbonyl, methoxycarbonyl or    carboxy;-   R⁶ is hydrogen, methyl-O-carbonyl or carboxymethyl;-   Y is —N(R⁷)—,    -   wherein R⁷ is hydrogen, methyl, difluoroethyl, isopropyl,        isobutyl, t-butyl, cyclopropyl, cyclopropylmethyl,        methyl-O-carbonylisopropyl, carboxyethyl, carboxydifluoroethyl,        carboxypropyl, carboxybutyl, carboxy(gemdimethyl)methyl,        carboxy(gemdimethyl)ethyl, carboxy(gemdimethyl)propyl,        carboxy(gemdimethyl)butyl, carboxy(methyl)ethyl,        carboxy(ethyl)ethyl, carboxy(methoxy)ethyl, carboxycyclobutyl,        carboxycyclobutylmethyl, carboxycyclopentyl, carboxycyclohexyl,        carboxymethylcyclopropyl, carboxycyclopropylmethyl,        carboxycyclobutylmethyl, carboxyspiro[3.3]heptyl,        carboxymethoxyethyl, carboxymethoxypropyl, hydroxyethyl,        hydroxymethyl(gemdimethyl)butyl, hydroxy(gemdimethyl)ethyl,        carboxyphenyl, carboxypyridinyl or carboxyphenylmethyl;-   W is —CH₂— or carbonyl.

Another embodiment of the present invention is (v) a compound of formula(IAA),

wherein

-   R¹ is halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen, aminocarbonyl or carboxy;-   R⁶ is hydrogen;-   R⁷ is C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₇cycloalkyl,    C₃₋₇cycloalkyl-C_(m)H_(2m)—, —C_(t)H_(2t)—COOH,    —C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH or carboxyphenyl;-   m is 0-7;-   t is 1-7;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

A further embodiment of the present invention is (vi) a compound offormula (I), (IA) or (IAA) or pharmaceutically acceptable salts, orenantiomers or diastereomers thereof, wherein

-   R¹ is chloro or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen, aminocarbonyl or carboxy;-   R⁶ is hydrogen;-   R⁷ is methyl, isopropyl, isobutyl, t-butyl, difluoroethyl,    cyclopropyl, cyclopropylmethyl, carboxy(gemdimethyl)ethyl,    carboxy(gemdimethyl)propyl, carboxycyclopropylmethyl,    carboxycyclobutylmethyl or carboxyphenyl.

Another embodiment of the present invention is (vii) a compound offormula (IB),

-   wherein-   R¹ is hydrogen or halogen;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen;-   R⁶ is hydrogen or carboxymethyl;-   Y is —CH₂— or —O—;-   W is —CH₂—, —C(C₁₋₆alkyl)₂- or —O—;-   n is 0 or 1;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

A further embodiment of the present invention is (viii) a compoundaccording to formula (I) or (IB) or pharmaceutically acceptable salts,or enantiomers or diastereomers thereof, wherein

-   R¹ is hydrogen, chloro or bromo;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen;-   R⁶ is hydrogen or carboxymethyl;-   Y is —CH₂— or —O—;-   W is —CH₂—, —C(CH₃)₂— or —O—;-   n is 0 or 1.

Another embodiment of the present invention is (ix) a compound offormula (ID)

wherein

-   R¹ is halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen, aminocarbonyl or carboxy;-   R⁶ is hydrogen or C₁₋₆alkoxycarbonyl-   X is carbonyl;-   Y is —O— or —N(R⁷)— or —CH₂—,    -   wherein R⁷ is hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl,        C₃₋₇cycloalkyl, C₃₋₇cycloalkyl-C_(m)H_(2m)—,        —C_(t)H_(2t)—COOH—C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH,        hydroxy-C_(t)H_(2t)—, carboxyspiro[3.3]heptyl or        carboxyphenyl-C_(m)H_(2m)—;-   m is 0-7;-   t is 1-7;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

A further embodiment of the present invention is (x) a compoundaccording to formula (I) or (ID), or pharmaceutically acceptable salts,or enantiomers or diastereomers thereof, wherein

-   R¹ is chloro, bromo or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl, ethyl or propyl;-   R⁵ is hydrogen, aminocarbonyl or carboxy;-   R⁶ is hydrogen or methyl-O-carbonyl;-   X is carbonyl;-   Y is —O—, —N(R⁷)— or —CH₂—,    -   wherein R⁷ is hydrogen, methyl, isopropyl, difluoroethyl,        isobutyl, t-butyl, cyclopropyl, cyclopropylmethyl,        carboxy(gemdimethyl)ethyl, carboxy(methyl)ethyl,        carboxycyclopropylmethyl, carboxyphenyl, carboxycyclopentyl,        carboxycyclohexyl, carboxy(gemdimethyl)propyl,        carboxy(gemdimethyl)butyl, carboxycyclobutylmethyl,        carboxyspiro[3.3]heptyl, hydroxyethyl, hydroxy(gemdimethyl)ethyl        or carb oxyphenylmethyl.

Another embodiment of the present invention is (xi) a compound offormula (IE),

wherein

-   R¹ is halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen or carboxy-C_(m)H_(2m)—;-   Y is —O—, —N(R⁷)— or —CH₂—,    -   wherein R⁷ is C₁₋₆alkyl, C₃₋₇cycloalkyl, —C_(t)H_(2t)—COOH,        —C₃₋₇cycloalkyl-C_(m)H_(2m)—COOH,        —C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH, —(C₁₋₆alkoxy)C₁₋₆alkyl-COOH,        —C₁₋₆alkyl-O—C₁₋₆alkyl-COOH, carboxyspiro[3.3]heptyl or        carboxyphenyl-C_(m)H_(2m)—;-   W is —CH₂— or —C(C₁₋₆alkyl)₂-;-   m is 0-7;-   t is 1-7;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

A further embodiment of the present invention is (xii) a compound offormula (I) or (IE) or pharmaceutically acceptable salts, or enantiomersor diastereomers thereof, wherein

-   R¹ is chloro or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen or carboxymethyl;-   Y is —O—, —N(R⁷)— or —CH₂—,    -   wherein R⁷ is isopropyl, methyl, isobutyl, t-butyl, cyclopropyl,        carboxyethyl, carboxypropyl, carboxybutyl,        carboxy(gemdimethyl)methyl, carboxy(gemdimethyl)ethyl,        carboxy(methyl)ethyl, carboxycyclobutyl,        carboxycyclopropylmethyl, carboxycyclopentyl, carboxycyclohexyl,        carboxymethylcyclopropyl, carboxy(gemdimethyl)propyl,        carboxy(ethyl)ethyl, carboxy(methoxy)ethyl,        carboxycyclobutylmethyl, carboxyspiro[3.3]heptyl,        carboxymethoxyethyl, carboxymethoxypropyl, carboxyphenylmethyl        or carboxyphenyl;-   W is —CH₂— or —C(CH₃)₂—.

Another embodiment of the present invention is (xiii) a compound offormula (IE),

wherein

-   R¹ is halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen or carboxy-C_(m)H_(2m)—;-   Y is —N(R⁷)—,    -   wherein R⁷ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,        —C_(t)H_(2t)—COOH, —C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH or        carboxyphenyl;-   W is —CH₂—;-   m is 0-7;-   t is 1-7;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

A further embodiment of the present invention is (xiv) a compoundaccording to formula (I) or (IE), or pharmaceutically acceptable salts,or enantiomers or diastereomers thereof, wherein

-   R¹ is chloro or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen or carboxymethyl;-   Y is —N(R⁷)—,    -   wherein R⁷ is hydrogen, methyl, t-butyl, cyclopropyl,        carboxy(gemdimethyl)ethyl, carboxy(gemdimethyl)propyl,        carboxy(methyl)ethyl, carboxycyclopropylmethyl,        carboxycyclopentyl, carboxycyclohexyl, carboxycyclobutylmethyl        or carboxyphenyl;-   W is —CH₂—.

Another embodiment of the present invention is (xv) a compound offormula (I), (IA), (IAA), (IB), (ID) or (IE) or pharmaceuticallyacceptable salts, or enantiomers or diastereomers, wherein the2-thiazolyl group is further substituted by C₁₋₆alkyl, and all the othersubstituents are defined as above.

A further embodiment of the present invention is (xvi) a compound offormula (I), (IA), (IAA), (IB), (ID) or (IE) or pharmaceuticallyacceptable salts, or enantiomers or diastereomers, wherein the2-thiazolyl group is further substituted by methyl, and all the othersubstituents are defined as above.

Another embodiment of the present invention is (xvii) compounds havingthe general formula (I):

wherein

-   R¹ is hydrogen, halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen, C₁₋₆alkoxycarbonyl or carboxy-C_(m)H_(2m)—;-   X is carbonyl or sulfonyl;-   Y is —CH₂—, —O— or —N(R⁷)—,    -   wherein R⁷ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,        C₁₋₆alkoxycarbonyl-C_(m)H_(2m)—, —C_(m)H_(2m)—COOH,        —(C₁₋₆alkoxy)C₁₋₆alkyl-COOH, —C₁₋₆alkyl-O—C₁₋₆alkyl-COOH, —C₃₋₇        cycloalkyl-C_(m)H_(2m)—COOH, —C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH,        hydroxy-C_(m)H_(2m)—, carboxyspiro[3.3]heptyl or        carboxyphenyl-C_(m)H_(2m)—;-   W is —CH₂—, —C(C₁₋₆alkyl)₂-, —O— or carbonyl;-   n is 0 or 1;-   m is 0-7;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Further embodiment of present invention is (xviii) a compound of formula(I), wherein

-   R¹ is hydrogen, chloro, bromo or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen, chloro or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen, methyl-O-carbonyl or carboxymethyl;-   X is carbonyl or sulfonyl;-   Y is —CH₂—, —O—, —N(R⁷)—,    -   wherein R⁷ is hydrogen, methyl, isopropyl, t-butyl, cyclopropyl,        methyl-O-carbonylisopropyl, carboxyethyl, carboxypropyl,        carboxybutyl, carboxy(gemdimethyl)methyl,        carboxy(gemdimethyl)ethyl, carboxy(gemdimethyl)propyl,        carboxy(gemdimethyl)butyl, carboxy(methyl)ethyl,        carboxy(ethyl)ethyl, carboxy(methoxy)ethyl, carboxycyclobutyl,        carboxycyclobutylmethyl, carboxycyclopentyl, carboxycyclohexyl,        carboxymethylcyclopropyl, carboxycyclopropylmethyl,        carboxycyclobutylmethyl, carboxyspiro[3.3]heptyl,        carboxymethoxyethyl, carboxymethoxypropyl, hydroxyethyl,        hydroxymethyl(gemdimethyl)butyl, carboxyphenyl or        carboxyphenylmethyl;-   W is —CH₂—, —C(CH₃)₂—, —O— or carbonyl;-   n is 0 or 1;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Another embodiment of present invention is (xix) a compound of formula(IA)

wherein

-   R¹ is halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen, C₁₋₆alkoxycarbonyl or carboxy-C_(m)H_(2m)—;-   Y is —N(R⁷)—,    -   wherein R⁷ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,        C₁₋₆alkoxycarbonyl-C_(m)H_(2m)—, —C_(m)H_(2m)—COOH,        —(C₁₋₆alkoxy)C₁₋₆alkyl-COOH, —C₁₋₆alkyl-O—C₁₋₆alkyl-COOH, —C₃₋₇        cycloalkyl-C_(m)H_(2m)—COOH, —C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH,        hydroxy-C_(m)H_(2m)—, carboxyspiro[3.3]heptyl or        carboxyphenyl-C_(m)H_(2m)—;-   W is —CH₂— or carbonyl;-   m is 0-7;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Further embodiment of present invention is (xx) a compound of formula(IA) or pharmaceutically acceptable salts, or enantiomers ordiastereomers thereof, wherein

-   R¹ is chloro, bromo or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen, chloro or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen, methyl-O-carbonyl or carboxymethyl;-   Y is —N(R⁷)—,    -   wherein R⁷ is hydrogen, methyl, isopropyl, t-butyl, cyclopropyl,        methyl-O-carbonylisopropyl, carboxyethyl, carboxypropyl,        carboxybutyl, carboxy(gemdimethyl)methyl,        carboxy(gemdimethyl)ethyl, carboxy(gemdimethyl)propyl,        carboxy(gemdimethyl)butyl, carboxy(methyl)ethyl,        carboxy(ethyl)ethyl, carboxy(methoxy)ethyl, carboxycyclobutyl,        carboxycyclobutylmethyl, carboxycyclopentyl, carboxycyclohexyl,        carboxymethylcyclopropyl, carboxycyclopropylmethyl,        carboxycyclobutylmethyl, carboxyspiro[3.3]heptyl,        carboxymethoxyethyl, carboxymethoxypropyl, hydroxyethyl,        hydroxymethyl(gemdimethyl)butyl, carboxyphenyl or        carboxyphenylmethyl;-   W is —CH₂— or carbonyl.

Another embodiment of present invention is (xxi) a compound of formula(IAA)

wherein

-   R¹ is halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen;-   R⁷ is C₁₋₆alkyl, C₃₋₇cycloalkyl, —C_(m)H_(2m)—COOH,    —C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH or carboxyphenyl;-   m is 1-6;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Further embodiment of present invention is (xxii) a compound of formula(IAA) or pharmaceutically acceptable salts, or enantiomers ordiastereomers thereof, wherein

-   R¹ is chloro or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen;-   R⁷ is methyl, isopropyl, t-butyl, cyclopropyl,    carboxy(gemdimethyl)ethyl, carboxy(gemdimethyl)propyl,    carboxycyclopropylmethyl, carboxycyclobutylmethyl or carboxyphenyl.

Another embodiment of present invention is (xxiii) a compound of formula(IC)

wherein

-   R¹ is halogen;-   R² is hydrogen;-   R³ is halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen;-   R⁶ is hydrogen;-   R⁷ is hydrogen;-   W is —CH₂—;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Another embodiment of present invention is (xxiv) a compound of formula(ID)

wherein

-   R¹ is halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen or C₁₋₆alkoxycarbonyl;-   X is carbonyl;-   Y is —O— or —N(R⁷)—,    -   wherein R⁷ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,        —C_(m)H_(2m)—COOH, —C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH,        hydroxy-C_(m)H_(2m)—, carboxyspiro[3.3]heptyl or        carboxyphenyl-C_(t)H_(2t)—;-   m is 1-6;-   t is 0-6;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Further embodiment of present invention is (xxv) a compound of formula(ID) or pharmaceutically acceptable salts, or enantiomers ordiastereomers thereof, wherein

-   R¹ is chloro, bromo or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen or methyl-O-carbonyl;-   X is carbonyl;-   Y is —O—, —N(R⁷)—,    -   wherein R⁷ is hydrogen, methyl, isopropyl, t-butyl cyclopropyl,        carboxy(gemdimethyl)ethyl, carboxy(methyl)ethyl,        carboxycyclopropylmethyl, carboxyphenyl, carboxycyclopentyl,        carboxycyclohexyl, carboxy(gemdimethyl)propyl,        carboxy(gemdimethyl)butyl, carboxycyclobutylmethyl,        carboxyspiro[3.3]heptyl, hydroxyethyl or carboxyphenylmethyl.

Another embodiment of present invention is (xxvi) a compound of formula(IE)

wherein

-   R¹ is halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen or carboxy-C_(m)H_(2m)—;-   Y is —O— or —N(R⁷)—,    -   wherein R⁷ is C₁₋₆alkyl, C₃₋₇cycloalkyl, —C_(m)H_(2m)—COOH,        —C₃₋₇cycloalkyl-C_(m)H_(2m)—COOH,        —C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH, —(C₁₋₆alkoxy)C₁₋₆alkyl-COOH,        —C₁₋₆alkyl-O—C₁₋₆alkyl-COOH, carboxyspiro[3.3]heptyl or        carboxyphenyl-C_(m)H_(2m)—;-   W is —CH₂— or —C(C₁₋₆alkyl)₂-;-   m is 0-6;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Further embodiment of present invention is (xxvii) a compound of formula(IE) or pharmaceutically acceptable salts, or enantiomers ordiastereomers thereof, wherein

-   R¹ is chloro or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen or carboxymethyl;-   Y is —O— or —N(R⁷)—,    -   wherein R⁷ is isopropyl, methyl, t-butyl, cyclopropyl,        carboxyethyl, carboxypropyl, carboxybutyl,        carboxy(gemdimethyl)methyl, carboxy(gemdimethyl)ethyl,        carboxy(methyl)ethyl, carboxycyclobutyl,        carboxycyclopropylmethyl, carboxycyclopentyl, carboxycyclohexyl,        carboxymethylcyclopropyl, carboxy(gemdimethyl)propyl,        carboxy(ethyl)ethyl, carboxy(methoxy)ethyl,        carboxycyclobutylmethyl, carboxyspiro[3.3]heptyl,        carboxymethoxyethyl, carboxymethoxypropyl, carboxyphenylmethyl        or carboxyphenyl;-   W is —CH₂— or —C(CH₃)₂—.

Another embodiment of present invention is (xxviii) a compound offormula (IE)

wherein

-   R¹ is halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen or carboxy-C_(m)H_(2m)—;-   Y is —O—, —N(R⁷)— or —CH₂—,    -   wherein R⁷ is C₁₋₆alkyl, C₃₋₇cycloalkyl, —C_(m)H_(2m)—COOH,        —C₃₋₇cycloalkyl-C_(m)H_(2m)—COOH,        —C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH, carboxyspiro[3.3]heptyl,        —(C₁₋₆alkoxy)C₁₋₆alkyl-COOH, —C₁₋₆alkyl-O—C₁₋₆ alkyl-COOH,        carboxypyridinyl-C_(m)H_(2m)— or carboxyphenyl-C_(m)H_(2m)—;-   W is —CH₂— or —C(C₁₋₆alkyl)₂-;-   m is 0-6;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Further embodiment of present invention is (xxix) a compound of formula(IE) or pharmaceutically acceptable salts, or enantiomers ordiastereomers thereof, wherein

-   R¹ is chloro or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen or carboxymethyl;-   Y is —O—, —N(R⁷)— or —CH₂—,    -   wherein R⁷ is methyl, t-butyl, isopropyl, cyclopropyl,        carboxyethyl, carboxypropyl, carboxybutyl,        carboxy(gemdimethyl)methyl, carboxy(gemdimethyl)ethyl,        carboxy(methyl)ethyl, carboxycyclobutyl, carboxycyclopentyl,        carboxycyclohexyl, carboxycyclopropylmethyl,        carboxy(gemdimethyl)propyl, carboxy(gemdimethyl)butyl,        carboxy(ethyl)ethyl, carboxy(methoxy)ethyl,        carboxycyclobutylmethyl, carboxymethylcyclopropyl,        carboxyspiro[3.3]heptyl, carboxymethoxyethyl,        carboxymethoxypropyl, carboxyphenylmethyl, carboxypyridinyl or        carboxyphenyl;-   W is —CH₂— or —C(CH₃)₂—.

The present invention provides (xxx) novel compounds having the generalformula (I):

wherein

-   R¹ is hydrogen, halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen, C₁₋₆alkoxycarbonyl or carboxy-C_(m)H_(2m)—;-   X is carbonyl or sulfonyl;-   Y is —CH₂—; —O—; —NR⁷ or —N—R⁸—COOH;    -   wherein R⁷ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl or        C₁₋₆alkoxycarbonyl-C_(m)H_(2m)—;    -   R⁸ is —C_(m)H_(2m)—, —C_(t)H_(2t)— C₃₋₇cycloalkyl-C_(t)H_(2t)—        or phenyl;-   W is —CH₂—, —O— or carbonyl;-   n is 0 or 1;-   m is 1-6;-   t is 0-6;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Further embodiment of present invention is (xxxi) a compound of formula(I), wherein

-   R¹ is hydrogen, chloro, bromo or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen, methyl-O-carbonyl or carboxymethyl;-   X is carbonyl or sulfonyl;-   Y is —CH₂—; —O—; —NR⁷ or —N—R⁸—COOH;    -   wherein R⁷ is hydrogen, isopropyl, cyclopropyl or        methyl-O-carbonylisopropyl;    -   R⁸ is ethyl, propyl, (gemdimethyl)methyl, (gemdimethyl)ethyl,        (methyl)ethyl, cyclobutyl, cyclopentyl, cyclohexyl,        methylcyclopropyl, cyclopropylmethyl, cyclobutylmethyl or        phenyl;-   W is —CH₂—, —O— or carbonyl;-   n is 0 or 1;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Another embodiment of present invention is (xxxii) a compound of formula(I), wherein

-   R¹ is hydrogen, halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen, C₁₋₆alkoxycarbonyl or carboxy-C_(m)H_(2m)—;-   X is carbonyl or sulfonyl;-   Y is —CH₂—; —O—; —NR⁷ or —N—R⁸—COOH;    -   wherein R⁷ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl or        C₁₋₆alkoxycarbonyl-C_(m)H_(2m)—;    -   R⁸ is —C_(m)H_(2m)—, C₃₋₇cycloalkyl-C_(t)H_(2t)— or phenyl;-   W is —CH₂—, —O— or carbonyl;-   n is 0 or 1;-   m is 1-6;-   t is 0-6;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Further embodiment of present invention is (xxxiii) a compound offormula (I), wherein

-   R¹ is hydrogen, chloro, bromo or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen, methyl-O-carbonyl or carboxymethyl;-   X is carbonyl or sulfonyl;-   Y is —CH₂—; —O—; —NR⁷ or —N—R⁸—COOH;    -   wherein R⁷ is hydrogen, isopropyl, cyclopropyl or        methyl-O-carbonylisopropyl;    -   R⁸ is (gemdimethyl)methyl, (gemdimethyl)ethyl, (methyl)ethyl,        cyclobutyl, cyclopropylmethyl or phenyl;-   W is —CH₂—, —O— or carbonyl;-   n is 0 or 1;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Another embodiment of present invention is (xxxiv) a compound of formula(IA)

wherein

-   R¹ is halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen, C₁₋₆alkoxycarbonyl or carboxy-C_(m)H_(2m)—;-   Y is —NR⁷ or —N—R⁸—COOH;    -   wherein R⁷ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl or        C₁₋₆alkoxycarbonyl-C_(m)H_(2m)—;    -   R⁸ is —C_(m)H_(2m)—, C₃₋₇cycloalkyl-C_(t)H_(2t)— or phenyl;-   W is —CH₂— or carbonyl;-   m is 1-6;-   t is 0-6;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Further embodiment of present invention is (xxxv) a compound of formula(IA) or pharmaceutically acceptable salts, or enantiomers ordiastereomers thereof, wherein

-   R¹ is chloro, bromo or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen, methyl-O-carbonyl or carboxymethyl;-   Y is —NR⁷ or —N—R⁸—COOH;    -   wherein R⁷ is hydrogen, isopropyl, cyclopropyl or        methyl-O-carbonylisopropyl;    -   R⁸ is (gemdimethyl)methyl, (gemdimethyl)ethyl, (methyl)ethyl,        cyclobutyl, cyclopropylmethyl or phenyl;-   W is —CH₂— or carbonyl.

Another embodiment of present invention is (xxxvi) a compound of formula(IAB)

wherein

-   R¹ is halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen;-   R⁶ is hydrogen;-   R⁸ is —C_(m)H_(2m)—, C₃₋₇cycloalkyl-C_(m)H_(2m)— or phenyl;-   m is 1-6;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Further embodiment of present invention is (xxxvii) a compound offormula (IAB) or pharmaceutically acceptable salts, or enantiomers ordiastereomers thereof, wherein

-   R¹ is chloro or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen;-   R⁶ is hydrogen;-   R⁸ is (gemdimethyl)ethyl, cyclopropylmethyl or phenyl.

Another embodiment of present invention is (xxxviii) a compound offormula (ID)

wherein

-   R¹ is halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen, C₁₋₆alkoxycarbonyl or carboxy-C_(m)H_(2m)—;-   X is carbonyl or sulfonyl;-   Y is —O—; —NR⁷ or —N—R⁸—COOH;    -   wherein R⁷ is hydrogen, C₁₋₆alkyl or C₃₋₇cycloalkyl;    -   R⁸ is —C_(m)H_(2m)—, C₃₋₇cycloalkyl-C_(t)H_(2t)— or phenyl;-   m is 1-6;-   t is 0-6;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Further embodiment of present invention is (xxxix) a compound of formula(ID) or pharmaceutically acceptable salts, or enantiomers ordiastereomers thereof, wherein

-   R¹ is chloro, bromo or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen, methyl-O-carbonyl or carboxymethyl;-   X is carbonyl or sulfonyl;-   Y is —O—; —NR⁷ or —N—R⁸—COOH;    -   wherein R⁷ is hydrogen, isopropyl or cyclopropyl;    -   R⁸ is (gemdimethyl)ethyl, (methyl)ethyl, cyclobutyl,        cyclopropylmethyl or phenyl.

Another embodiment of present invention is (xl) a compound of formula(IF)

wherein

-   R¹ is halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen or carboxy-C_(m)H_(2m)—;-   Y is —NR⁷ or —N—R⁸—COOH;    -   wherein R⁷ is C₁₋₆alkyl or C₃₋₇cycloalkyl;    -   R⁸ is —C_(m)H_(2m)—, C₃₋₇cycloalkyl-C_(t)H_(2t)— or phenyl;-   m is 1-6;-   t is 0-6;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Further embodiment of present invention is (xli) a compound of formula(IF) or pharmaceutically acceptable salts, or enantiomers ordiastereomers thereof, wherein

-   R¹ is chloro or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen or carboxymethyl;-   Y is —NR⁷ or —N—R⁸—COOH;    -   wherein R⁷ is isopropyl or cyclopropyl;    -   R⁸ is (gemdimethyl)methyl, (gemdimethyl)ethyl, (methyl)ethyl,        cyclobutyl, cyclopropylmethyl or phenyl.

Another embodiment of present invention is (xxxxii) a compound offormula (IF)

wherein

-   R¹ is halogen or C₁₋₆alkyl;-   R² is hydrogen or halogen;-   R³ is hydrogen or halogen;-   R⁴ is C₁₋₆alkyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen or carboxy-C_(m)H_(2m)—;-   Y is —NR⁷ or —N—R⁸—COOH;    -   wherein R⁷ is hydrogen or C₃₋₇cycloalkyl;    -   R⁸ is —C_(m)H_(2m)—, C₃₋₇cycloalkyl-C_(m)H_(2m)— or phenyl;-   m is 1-6;    or pharmaceutically acceptable salts, or enantiomers or    diastereomers thereof.

Further embodiment of present invention is (xliii) a compound of formula(IE) or pharmaceutically acceptable salts, or enantiomers ordiastereomers thereof, wherein

-   R¹ is chloro or methyl;-   R² is hydrogen or fluoro;-   R³ is hydrogen or fluoro;-   R⁴ is methyl or ethyl;-   R⁵ is hydrogen or carboxy;-   R⁶ is hydrogen or carboxymethyl;-   Y is —NR⁷ or —N—R⁸—COOH;    -   wherein R⁷ is hydrogen or cyclopropyl;    -   R⁸ is (gemdimethyl)ethyl, (methyl)ethyl, cyclopropylmethyl or        phenyl.

Further embodiment of present invention is (xliv) a compound of formula(I), formula (IA), formula (IAA), formula (IB), formula (IC), formula(ID), formula (IE), formula (IAB), or formula (IF) or pharmaceuticallyacceptable salts, or enantiomers or diastereomers thereof, whereinchirality at 4-position of dihydropyrimidine core is the same as formula(I-R) below, and R¹, R², R³, R⁴, R⁵, R⁶, X, Y, W and n are as defined inany one of the above embodiment (i) to (xliii).

Particular compounds of the present invention according to the inventionare the following:

-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-oxo-1,3,4,8,9,9a-hexahydropyrazino[1,2-c][1,3]oxazin-2-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(4-oxo-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-6-[[(8aR)-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-6-[[(8aS)-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-6-[[(8aS)-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-6-[[(8aR)-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-6-[[(8aR)-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl]methyl]-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Ethyl    (4R)-6-[[(8aR)-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl]methyl]-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Ethyl    (4S)-6-[[(8aR)-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl]methyl]-4-(3,4-difluorophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Ethyl    (4R)-4-(2-chloro-3-fluoro-phenyl)-6-[(6-oxo-3,4,7,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-6-[[(8aR)-3-oxo-1,2,5,6,8,8a-hexahydroimidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-6-[[(8aS)-3-oxo-1,2,5,6,8,8a-hexahydroimidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Ethyl    (4R)-6-[[(8aS)-3-oxo-1,2,5,6,8,8a-hexahydroimidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Ethyl    (4R)-6-[[(8aR)-3-oxo-1,2,5,6,8,8a-hexahydroimidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-6-[[(8aR)-1,3-dioxo-5,6,8,8a-tetrahydroimidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-6-[[(8aS)-1,3-dioxo-5,6,8,8a-tetrahydroimidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-6-[[(3aS)-1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazin-5-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-6-[[(3aR)-1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazin-5-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   3-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid;-   3-[(8aS)-7-[[(4R)-4-(2-chlorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-H-imidazo[1,5-a]pyrazin-2-yl]-2-methyl-propanoic    acid;-   3-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-H-imidazo[1,5-a]pyrazin-2-yl]-2-methyl-propanoic    acid;-   3-[(8aS)-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid;-   Ethyl    (4R)-4-(2-chloro-3-fluoro-phenyl)-6-[[2-(2-methoxyl-1,1-dimethyl-2-oxo-ethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-2,5,6,8-tetrahydro-1H-imidazo[1,5-a]pyrazine-8a-carboxylate;-   (R)-6-[(S)-2-(4-Carboxy-phenyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-6-[(S)-2-(4-Carboxy-phenyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   (R)-6-[(S)-2-(3-Carboxy-phenyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   (R)-6-[(S)-2-(2-Carboxy-phenyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   (R)-6-[(S)-2-(3-Carboxy-phenyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   2-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-cyclopropyl-3-oxo-1,5,6,8-tetrahydroimidazo[1,5-a]pyrazin-8a-yl]acetic    acid;-   2-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isopropyl-3-oxo-1,5,6,8-tetrahydroimidazo[1,5-a]pyrazin-8a-yl]acetic    acid;-   (R)-6-[(S)-2-(1-Carboxyl-1-methyl-ethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   3-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazo-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-3-methyl-butanoic    acid;-   3-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-3-methyl-butanoic    acid;-   1-[[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]methyl]cyclopropanecarboxylic    acid;-   1-[[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]methyl]cyclopropanecarboxylic    acid;-   3-[(8aS)-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-3-methyl-butanoic    acid;-   1-[[(8aS)-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]methyl]cyclopropanecarboxylic    acid;-   3-[(2S,8aR)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclobutanecarboxylic    acid;-   3-[(8aR)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclobutanecarboxylic    acid;-   3-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid;-   3-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid;-   3-[(8aS)-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid;-   3-[(8aS)-7-[[(4S)-4-(3-fluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid; and-   7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid.-   2-[1-[(8aR)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclopropyl]acetic    acid;-   2-[1-[(8aR)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclopropyl]acetic    acid;-   2-[1-[(8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclopropyl]acetic    acid;-   (1R,2R)-2-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylic    acid;-   (1S,2R)-2-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylic    acid;-   (1R,2S)-2-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylic    acid;-   (1S,2S)-2-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylic    acid;-   4-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]butanoic    acid;-   4-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-butanoic    acid;-   4-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-3,3-dimethyl-butanoic    acid;-   (R)-6-[(S)-2-(2-Carboxy-ethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   (R)-6-[(S)-2-((R)-2-Carboxyl-1-methyl-ethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   (R)-6-[(S)-2-((S)-2-Carboxyl-1-methyl-ethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   (R)-6-[(S)-2-(1-Carboxy-cyclobutylmethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   6-[(S)-2-(1-Carboxy-cyclobutylmethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-((R)-2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   (R)-6-[(S)-2-((1R,3S)-3-Carboxy-cyclopentyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-6-[(S)-2-((R)-(S)-3-Carboxy-cyclopentyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   (R)-6-[(S)-2-((1R,3R)-3-Carboxy-cyclopentyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-6-[(S)-2-((1R,3R)-3-Carboxy-cyclopentyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   (R)-6-[2-(4-Carboxy-benzyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-6-[2-(4-Carboxy-benzyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   2-[2-[7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]ethoxy]acetic    acid;-   2-[3-[7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]propoxy]acetic    acid;-   methyl    (4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[2-(5-hydroxy-4,4-dimethyl-pentyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   ethyl    (4R)-4-(2-chloro-3-fluoro-phenyl)-6-[[2-(2-hydroxyethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   ethyl    (4R)-4-(2-chloro-3-fluoro-phenyl)-6-[[2-(2-hydroxyethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   4-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclohexanecarboxylic    acid;-   4-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclohexanecarboxylic    acid;-   3-[(8aS)-7-[[(4R)-4-(2-chlorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid;-   2-[[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]methyl]butanoic    acid;-   3-[(8aS)-7-[[(4S)-5-ethoxycarbonyl-4-(3-fluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid;-   3-[(8aS)-7-[[4-(4-chlorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid;-   3-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2-methoxy-propanoic    acid;-   2-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]spiro[3.3]heptane-6-carboxylic    acid;-   5-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]pentanoic    acid;-   3-[[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]methyl]cyclobutanecarboxylic    acid;-   (8R,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8R,8aS)-2-cyclopropyl-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-2-cyclopropyl-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8R,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8R,8aS)-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8R,8aS)-2-tert-butyl-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-2-tert-butyl-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8R,8aS)-2-tert-butyl-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-2-tert-butyl-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8R,8aS)-2-tert-butyl-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-2-tert-butyl-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   methyl    (8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-2,5,6,8-tetrahydro-1H-imidazo[1,5-a]pyrazine-8a-carboxylate;-   2-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-1,1-dimethyl-3-oxo-6,8-dihydro-5H-oxazolo[3,4-a]pyrazin-8a-yl]acetic    acid;-   2-[(8aR)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-1,1-dimethyl-3-oxo-6,8-dihydro-5H-oxazolo[3,4-a]pyrazin-8a-yl]acetic    acid;-   (8S,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8R,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   Methyl    (4R)-6-[[(8R,8aS)-2-tert-butyl-8-carbamoyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-6-[[(8S,8aR)-2-tert-butyl-8-carbamoyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   3-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-propoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid;-   4-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-butanoic    acid;-   5-[7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]pyridine-2-carboxylic    acid;-   (S)-6-[(S)-2-(2-Carboxy-2,2-difluoro-ethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(3,4-difluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   (8R,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-(cyclopropylmethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-(cyclopropylmethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   3-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-(4-methylthiazol-2-yl)-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid;-   2-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1-carboxylic    acid;-   (8R,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isobutyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isobutyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8R,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-8-carboxylic    acid;-   (8S,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-8-carboxylic    acid;-   Ethyl    (4R)-6-[[(8R,8aS)-2-tert-butyl-8-(hydroxymethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Ethyl    (4R)-6-[[(8S,8aR)-2-tert-butyl-8-(hydroxymethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Ethyl    (4R)-6-[[(8aR)-2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;    and-   Ethyl    (4R)-6-[[(8aS)-2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   (8R,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-(2,2-difluoroethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-(2,2-difluoroethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   Ethyl    (4R)-6-[[(8aR)-2-(2-hydroxy-2-methyl-propyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   and Ethyl    (4R)-6-[[(8aS)-2-(2-hydroxy-2-methyl-propyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;

or pharmaceutically acceptable salts, or enantiomers or diastereomersthereof.

More particular compounds of the present invention are the following:

-   3-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid;-   3-[(8aS)-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid;-   (R)-6-[(S)-2-(4-Carboxy-phenyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   (R)-6-[(S)-2-(4-Carboxy-phenyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   (R)-6-[(S)-2-(3-Carboxy-phenyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   (R)-6-[(S)-2-(3-Carboxy-phenyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   3-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-3-methyl-butanoic    acid;-   1-[[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]methyl]cyclopropanecarboxylic    acid;-   1-[[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]methyl]cyclopropanecarboxylic    acid;-   1-[[(8aS)-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]methyl]cyclopropanecarboxylic    acid;-   3-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid; and-   3-[(8aS)-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid;-   4-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-butanoic    acid;-   4-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-3,3-dimethyl-butanoic    acid;-   (R)-6-[(S)-2-(1-Carboxy-cyclobutylmethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid methyl ester;-   6-[(S)-2-(1-Carboxy-cyclobutylmethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-((R)-2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic    acid ethyl ester;-   3-[(8aS)-7-[[(4S)-5-ethoxycarbonyl-4-(3-fluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic    acid;-   (8S,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-2-cyclopropyl-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-2-tert-butyl-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-2-tert-butyl-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-2-tert-butyl-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8R,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   Methyl    (4R)-6-[[(8R,8aS)-2-tert-butyl-8-carbamoyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   Methyl    (4R)-6-[[(8S,8aR)-2-tert-butyl-8-carbamoyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;-   4-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-butanoic    acid;-   (8R,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-(cyclopropylmethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   (8S,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-(cyclopropylmethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;-   2-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1-carboxylic    acid;-   (8R,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-8-carboxylic    acid;-   (8S,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-8-carboxylic    acid;-   (8R,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-(2,2-difluoroethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid; and-   (8S,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-(2,2-difluoroethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylic    acid;

or pharmaceutically acceptable salts, or enantiomers or diastereomers.

Synthesis

The compounds of the present invention can be prepared by anyconventional means. Suitable processes for synthesizing these compoundsas well as their starting materials are provided in the schemes belowand in the examples. All substituents, in particular, R¹ to R⁶, X, Y, Wand n are as defined above unless otherwise indicated. Furthermore, andunless explicitly otherwise stated, all reactions, reaction conditions,abbreviations and symbols have the meanings well known to a person ofordinary skill in organic chemistry.

General Synthetic Route for Compound I (Scheme 1)

Compound of interest I can be prepared according to Scheme 1. A one-potreaction between acetyl acetate II, benzaldehyde III and thiazoleamidine IV gives dihydropyrimidine V. (−)-Enantiomer Va is then obtainedby SFC chiral separation of V and its stereochemistry is determined bycomparing its SFC retention time with one of its particular Compound B1which stereochemistry is determined by X-ray diffraction study (FIG. 1).Bromination of Va affords VI. Coupling VI with a suitable fused amineVII gives the compound of interest I.

Dihydropyrimidine V can be prepared from condensation and cyclizationsequence of acetyl acetate II, aldehyde III and thiazole amidine IV. Thereaction can be carried out in a suitable alcoholic solvent such astrifluoroethanol in the presence of a base such as potassium acetateunder a heating condition over several hours.

(−)-Enantiomer Va is obtained by SFC chiral separation of V.

Bromide VI can be prepared by reaction of Va with a bromination reagentsuch as N-bromosuccinimide, in a suitable inert solvent such as carbontetrachloride at 80-100 degrees Celsius.

Compound of interest I can be obtained by coupling bromide VI with afused amine VII. The reaction is typically performed in a suitablesolvent such as 1,2-dichloroethane at room temperature over severalhours in the presence of an organic base such asN,N-diisopropylethylamine.

General Synthetic Route for the Diastereoisomer Mixture of Compound I-I(Scheme 1-1)

Compound of interest I-I can be prepared in analogy to compound ofinterest I without SFC chiral separation of dihydropyrimidine V.

For scheme 1 or scheme 1-1, the 2-thiazolyl group of general formula(I), (V), (Va), (Vb), (VI), (VI-I), (I-I) and any other compounds ofthis invention can be further substituted by C₁₋₆ alkyl, such as methyl.

This invention also relates to a process for the preparation of acompound of formula (I) or other compounds of the present inventioncomprising the reaction of

(a) a compound of formula (A)

with

in the presence of a base;wherein R¹ to R⁶, X, Y, W and n are defined above unless otherwiseindicated.

In step (a), the base can be for example N,N-diisopropylethylamine.

A compound of formula (I) or other compounds of the present inventionwhen manufactured according to the above process is also an object ofthe invention.

Pharmaceutical Compositions and Administration

The invention also relates to a compound of formula (I) or othercompounds of the present invention for use as therapeutically activesubstance.

Another embodiment provides pharmaceutical compositions or medicamentscontaining the compounds of the invention and a therapeutically inertcarrier, diluent or excipient, as well as methods of using the compoundsof the invention to prepare such compositions and medicaments. In oneexample, compounds of formula (I) or other compounds of the presentinvention may be formulated by mixing at ambient temperature at theappropriate pH, and at the desired degree of purity, withphysiologically acceptable carriers, i.e., carriers that are non-toxicto recipients at the dosages and concentrations employed into agalenical administration form. The pH of the formulation depends mainlyon the particular use and the concentration of compound, but preferablyranges anywhere from about 3 to about 8. In one example, a compound offormula (I) or a compound of the present invention is formulated in anacetate buffer, at pH 5. In another embodiment, the compounds of formula(I) and other compounds of the present invention are sterile. Thecompound may be stored, for example, as a solid or amorphouscomposition, as a lyophilized formulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularhuman being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. The “effective amount” of the compoundto be administered will be governed by such considerations, and is theminimum amount necessary to the suppression of serum HBV DNA levels, orHBeAg seroconversion to HBeAb, or HBsAg loss, or normalization ofalanine aminotransferase levels and improvement in liver histology. Forexample, such amount may be below the amount that is toxic to normalcells, or the human as a whole.

In one example, the pharmaceutically effective amount of the compound ofthe invention administered parenterally per dose will be in the range ofabout 0.01 to 100 mg/kg, alternatively about 0.1 to 20 mg/kg of patientbody weight per day, with the typical initial range of compound usedbeing 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosageforms, such as tablets and capsules, contain from about 0.1 to about1000 mg of the compound of the invention.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier or excipient. Suitable carriers and excipientsare well known to those skilled in the art and are described in detailin, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Formsand Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice ofPharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,Raymond C. Handbook of Pharmaceutical Excipients. Chicago,Pharmaceutical Press, 2005. The formulations may also include one ormore buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents, diluents and other knownadditives to provide an elegant presentation of the drug (i.e., acompound of the present invention or pharmaceutical composition thereof)or aid in the manufacturing of the pharmaceutical product (i.e.,medicament).

An example of a suitable oral dosage form is a tablet containing about0.1 mg to 1000 mg of the compound of the invention compounded with about30 mg to 90 mg anhydrous lactose, about 5 mg to 40 mg sodiumcroscarmellose, about 5 mg to 30 mg polyvinylpyrrolidone (PVP) K30, andabout 1 mg to 10 mg magnesium stearate. The powdered ingredients arefirst mixed together and then mixed with a solution of the PVP. Theresulting composition can be dried, granulated, mixed with the magnesiumstearate and compressed to tablet form using conventional equipment. Anexample of an aerosol formulation can be prepared by dissolving thecompound, for example 5 mg to 400 mg, of the invention in a suitablebuffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. asalt such sodium chloride, if desired. The solution may be filtered,e.g., using a 0.2 micron filter, to remove impurities and contaminants.

An embodiment, therefore, includes a pharmaceutical compositioncomprising a compound of formula (I), or a stereoisomer orpharmaceutically acceptable salt thereof. In a further embodimentincludes a pharmaceutical composition comprising a compound of formula(I), or a stereoisomer or pharmaceutically acceptable salt thereof,together with a pharmaceutically acceptable carrier or excipient.

The following example A and B illustrate typical compositions of thepresent invention, but serve merely as representative thereof.

EXAMPLE A

A compound of the present invention can be used in a manner known per seas the active ingredient for the production of tablets of the followingcomposition:

Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mgCorn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

EXAMPLE B

A compound of the present invention can be used in a manner known per seas the active ingredient for the production of capsules of the followingcomposition:

Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mgIndications and Methods of Treatment

The compounds of the invention can inhibit HBV's de novo DNA synthesisand reduce HBV DNA levels. Accordingly, the compounds of the inventionare useful for the treatment or prophylaxis of HBV infection.

The compounds of inventions are useful as HBV capsid inhibitors.

The invention relates to the use of a compound of formula (I) or acompound of the present invention for the treatment or prophylaxis ofHBV infection.

The use of a compound of formula (I) or a compound of the presentinvention for the preparation of medicaments useful in the treatment orprophylaxis diseases that are related to HBV infection is an object ofthe invention.

The invention relates in particular to the use of a compound of formula(I) or a compound of the present invention for the preparation of amedicament for the treatment or prophylaxis of HBV infection.

Another embodiment includes a method for the treatment or prophylaxis ofHBV infection which method comprises administering an effective amountof a compound of formula (I), a stereoisomer, tautomer, prodrug orpharmaceutically acceptable salt thereof.

Combination Therapy

The compounds of the invention can be used together with interferon,pegylated interferons, Lamivudine, Adefovir dipivoxil, Entecavir,Telbivudine, and Tenofovir disoproxil for the treatment or prophylaxisof HBV.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1. X-ray crystal structure of Compound B1

EXAMPLES

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention.

Abbreviations used herein are as follows:

-   [α]_(D) ²⁰: optical rotation at 20 degrees Celsius-   BOMCl benzylchloromethyl ester-   calc'd: calculated-   CC₅₀: concentration results in the death of 50 percent of the cells-   CCK-8: cell counting kit-8-   CCl₄: carbon tetrachloride-   Ct: cycle threshold-   d: day-   DIPEA: N,N-diisopropylethylamine-   DCM: dichloromethylene-   PE: petroleum ether-   DMSO: dimethylsulfoxide-   DEA: diethyl amine-   DNA: deoxyribonucleic acid-   EtOH: ethanol-   EtOAc or EA: ethyl acetate-   g: gram-   EC₅₀: half maximal effective concentration-   h or hr: hour-   hrs: hours-   HAP: heteroaryldihydropyrimidine-   HATU:    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   HBeAb: hepatitis B e antibody-   HBeAg: hepatitis B e antigen-   HBsAg: hepatitis B surface antigen-   HCl: hydrogen chloride-   HPLC: high performance liquid chromatography-   HPLC-UV: high performance liquid chromatography with ultraviolet    detector-   Hz: hertz-   IPA: isopropanol-   LDA: lithium diisopropylamide-   METHANOL-d₄: deuterated methanol-   MeOH: methanol-   mg: milligram-   MHz: megahertz-   min: minute-   mins: minutes-   mL: milliliter-   mm: millimeter-   mM: mmol/L-   mmol: millimole-   MS: mass spectrometry-   MW: molecular weight-   Na₂SO₄: sodium sulfate-   NaOH: sodium hydroxide-   NBS: N-bromosuccinimide-   NMR: nuclear magnetic resonance-   PBS: phosphate buffered saline-   PD: pharmacodynamics-   PK: pharmacokinetics-   prep-HPLC: preparative high performance liquid chromatography-   rt: room temperature-   sat. saturated-   SFC: supercritical fluid chromatography-   TEA: triethylamine-   Tet: tetracycline-   TFA: trifluoroacetic acid-   THF: tetrahydrofuran-   μg: microgram-   μL: microliter-   μM: micromole-   UV: ultraviolet detector-   OD: optical density-   pgRNA: pre-genomic RNA-   qPCR: quantitative polymerase chain reaction-   qRT-PCR: quantitative real-time polymerase chain reaction-   CYP: cytochromes P450-   [Ir(COD)₂Cl]₂: bis(1,5-cyclooctadiene)diiridium(I) dichloride-   Cs₂CO₃: cesium carbonate-   Pd(OAc)₂: palladium(II) acetate-   NaBH₄: sodium borohydride-   RuCl₃: ruthenium(III) chloride    General Experimental Conditions

Intermediates and final compounds were purified by flash chromatographyusing one of the following instruments: i) Biotage SP1 system and theQuad 12/25 Cartridge module. ii) ISCO combi-flash chromatographyinstrument. Silica gel brand and pore size: i) KP-SIL 60 Å, particlesize: 40-60 μM; ii) CAS registry NO: Silica Gel: 63231-67-4, particlesize: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang ChemicalCo., Ltd, pore: 200-300 or 300-400.

Intermediates and final compounds were purified by preparative HPLC onreversed phase column using XBridge™ Prep-C18 (5 μm, OBD™ 30×100 mm)column or SunFire™ Prep-C18 (5 μm, OBD™ 30×100 mm) column. Waters AutoPpurification System (Column: XBridge™ Prep-C18, 30×100 mm, SampleManager 2767, Pump 2525, Detector: Micromass ZQ and UV 2487, solventsystem: acetonitrile and 0.1% ammonium hydroxide in water). For SFCchiral separation, intermediates were separated by chiral column (Daicelchiralpak IC, 5 μm, 30×250 mm) column using Mettler Toledo SFC-MultigramIII system, solvent system: 95% CO₂ and 5% IPA (0.5% TEA in IPA), backpressure 100 bar, detection UV@ 254 nm.

LC/MS spectra of compounds were obtained using a LC/MS (Waters™ Alliance2795-Micromass ZQ), LC/MS conditions were as follows (running time 6min):

Acidic condition: A: 0.1% formic acid in H₂O; B: 0.1% formic acid inacetonitrile;

Basic condition: A: 0.1% NH₃.H₂O in H₂O; B: acetonitrile;

Neutral condition: A: H₂O; B: acetonitrile.

Mass spectra (MS): generally only ions which indicate the parent massare reported, and unless otherwise stated the mass ion quoted is thepositive mass ion (MH)⁺.

NMR Spectra were obtained using Bruker Avance 400 MHz.

A single crystal was mounted in a loop and cooled to 160 K in a nitrogenstream. Data were collected on a Gemini R Ultra diffractometer (OxfordDiffraction, UK) with Cu-K-alpha-radiation (1.54178 Å) and processedwith the Crysalis-package. Structure solution and refinement wasperformed using the ShelXTL software (Bruker AXS, Karlsruhe)

The microwave assisted reactions were carried out in a Biotage InitiatorSixty microwave synthesizer.

All reactions involving air-sensitive reagents were performed under anargon atmosphere. Reagents were used as received from commercialsuppliers without further purification unless otherwise noted.

Preparative Examples

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention.

Example 1 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-oxo-1,3,4,8,9,9a-hexahydropyrazino[1,2-c][1,3]oxazin-2-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared according to the general syntheticroutes shown in Scheme 1. A detailed synthetic route is provided inScheme 2.

Preparation of Compound A

To a stirred solution of thiazole-2-carbonitrile (1.5 g, 14 mmol) in 5mL of dry MeOH was added dropwise a solution of sodium methoxide (0.74g, 14 mmol) in 10 mL of dry methanol. The reaction mixture was stirredat room temperature until the disappearance of starting material. Afterthat, ammonium chloride (1.5 g, 28 mmol) was added in one portion andthe reaction mixture was stirred overnight. The undissolved material wasremoved by filtration and the filtrate was concentrated to affordthiazole-2-carboxamidine hydrochloride (Compound A) as a grey solidwhich was used directly in the next step without further purification.MS: calc'd 128 (MH⁺), measured 128 (MH⁺).

Preparation of Compound B

To a stirred solution of thiazole-2-carboxamidine hydrochloride (0.13 g,1.0 mmol), methyl acetoacetate (0.12 g, 1.0 mmol) and2-chloro-4-fluorobenzaldehyde (0.16 g, 1.0 mmol) in trifluoroethanol (8mL) was added potassium acetate (0.20 g, 2.0 mmol). The reaction mixturewas refluxed for 16 hours. After it was cooled to room temperature, thereaction mixture was concentrated and the residue was dissolved in ethylacetate and then washed with brine. The organic layer was dried oversodium sulfate. The solvent was concentrated, and the residue waspurified by column chromatography (ethyl acetate/petroleum ether is from1/4 to 1/2) to afford4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound B) as a yellow solid. MS: calc'd(MH⁺) 366, measured (MH⁺) 366.

Preparation of Compound B1

The enantiomer(R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound B1) was obtained through SFC (SFC-Multigram;IC: 5×250 mm, 5μ) chiral separation of4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-oxazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound B) eluting with a mixed solvent of 85%supercritical CO₂/15% EtOH at 100 mL/min rate. The desired(−)-enantiomer B1 was eluted out before (+)-enantiomer B2. The absoluteconfiguration of (−)-enantiomer B1 was determined by X-ray diffractionstudy (FIG. 1).

Compound B1: [α]_(D) ²⁰ −55.0 (c 0.845, MeOH).

Compound B2: [α]_(D) ²⁰ +44.6 (c 0.175, MeOH).

Preparation of Compound C

To a stirred solution of(R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (0.37 g, 1.0 mmol) in CCl₄ (5 mL) was added NBS (0.20g, 1.1 mmol) in portions. After the reaction mixture was stirred at roomtemperature for 1 hour, the solvent was removed in vacuo and the residuewas purified by column chromatography to give(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) as a yellow solid. MS: calc'd 445 (MH⁺),measured 445 (MH⁺).

Preparation of hexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D)

Step 1: Methyl 4-boc-piperazine-2-acetate (CAS number: 183742-33-8,Chemfinder) (1.0 g, 4 mmol) was dissolved in 10 mL of MeOH, then NaBH₄(1.5 g, 40 mmol) was added portion wise and stirred overnight. Thesolvent was removed in vacuo and the residue was partitioned betweenEtOAC and water. The organic layer was separated, and then dried overNa₂SO₄ and concentrated to give3-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester ascrude oil (compound E), which was used directly without furtherpurification.

Step 2: 3-(2-Hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butylester (58 mg, 0.25 mmol) was dissolved in 4 mL of dichloromethane and 1mL of DIPEA, and then triphosgene (27 mg, 0.09 mmol) was added at roomtemperature. The reaction mixture was stirred for 30 minutes, and thesolvent was removed in vacuo. The residue was dissolved in 3 mL ofdichloromethane and 1 mL of TFA. After the reaction mixture was stirredfor 1 hour, the solvent was removed in vacuo to givehexahydro-pyrazino[1,2-c][1,3]oxazin-6-one trifluoro acetitic acid salt(Compound D) as a crude product which was used directly without furtherpurification. LC/MS: calc'd 157 (MH⁺), exp 157 (MH⁺).

Preparation of Example 1

To a stirred solution of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (0.072 g, 0.16 mmol) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one trifluoro acetitic acid salt(Compound D, crude, 0.25 mmol) in 1,2-dichloroethane (5 mL) was addeddropwise DIPEA (0.078 mL, 0.45 mmol). The reaction mixture was stirredat room temperature until the disappearance of starting material. Themixture was diluted with EtOAc (50 mL) and washed successively withsaturated aqueous NH₄Cl solution and brine. The organic layer wasseparated and then dried over Na₂SO₄. The solvent was concentrated invacuo and the crude product was purified by prep-HPLC to give methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-oxo-1,3,4,8,9,9a-hexahydropyrazino[1,2-c][1,3]oxazin-2-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Example 1) as a light yellow solid (11 mg). ¹H NMR (400 MHz,METHANOL-d₄) d ppm 7.97 (dd, J=3.01, 1.00 Hz, 1H), 7.81 (d, J=3.01 Hz,1H), 7.46 (dd, J=8.66, 6.15 Hz, 1H), 7.26 (dd, J=8.78, 2.51 Hz, 1H),7.00-7.13 (m, 1H), 6.19 (d, J=1.76 Hz, 1H), 4.19-4.48 (m, 4H), 4.11 (d,J=16.06 Hz, 1H), 3.76-3.94 (m, 1H), 3.62 (s, 3H), 3.18-3.31 (m, 2H),2.37-2.80 (m, 3H), 2.11-2.30 (m, 1H), 1.90 (qdd, J=14.37, 14.37, 14.37,9.22, 5.40 Hz, 1 H). MS: calc'd 520 (MH⁺), measured 520 (MH⁺).

Example 2 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(4-oxo-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 1 by using1,6,7,8,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-4-one (WuXi AppTec(Wuhan) Co., Ltd, catalog number: WX111240; for its synthesis, pleaserefer to: Tang, Pengcho et al., PCT Int. Appl., 2012019426) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 2 wasobtained as a light yellow solid (9 mg). ¹H NMR (400 MHz, METHANOL-d₄) dppm 7.96 (d, J=3.14 Hz, 1H), 7.76 (d, J=3.14 Hz, 1H), 7.43 (dd, J=8.72,6.09 Hz, 1H), 7.24 (dd, J=8.72, 2.57 Hz, 1H), 6.96-7.12 (m, 1H), 6.18(d, J=2.26 Hz, 1H), 4.46-4.66 (m, 1H), 4.05-4.22 (m, 3H), 3.77-4.05 (m,3H), 3.53-3.73 (m, 4H), 2.94-3.13 (m, 2H), 2.81-2.94 (m, 1H), 2.15-2.52(m, 2 H). MS: calc'd 520 (MH⁺), measured 520 (MH⁺).

Example 3 Methyl(4R)-6-[[(8aR)-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 1 by using(S)-4-N-Boc-2-hydroxymethyl-piperazine (CAS number: 314741-40-7,Bepharm) instead of 3-(2-hydroxy-ethyl)-piperazine-1-carboxylic acidtert-butyl ester (Compound E). Example 3 was obtained as a light yellowsolid (21 mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.93-8.00 (m, 1H),7.73-7.84 (m, 1H), 7.40-7.50 (m, 1H), 7.25 (dd, J=8.66, 2.64 Hz, 1H),7.00-7.12 (m, 1H), 6.15-6.22 (m, 1H), 4.42-4.57 (m, 1H), 4.25 (d,J=16.81 Hz, 1H), 4.13-4.22 (m, 1H), 3.99-4.13 (m, 2H), 3.78-3.90 (m,1H), 3.56-3.67 (m, 3H), 3.29-3.39 (m, 1H), 3.25 (d, J=9.03 Hz, 1H), 2.96(d, J=11.04 Hz, 1H), 2.30-2.61 (m, 2 H). MS: calc'd 506 (MH⁺), measured506 (MH⁺).

Example 4 Methyl(4R)-6-[[(8aS)-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 1 by using(R)-4-N-boc-2-hydroxymethyl-piperazine (CAS number: 278788-66-2,Bepharm) instead of 3-(2-hydroxy-ethyl)-piperazine-1-carboxylic acidtert-butyl ester (Compound E). Example 4 was obtained as a light yellowsolid (20 mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.92-8.00 (m, 1H),7.78 (d, J=3.26 Hz, 1H), 7.44 (dd, J=8.78, 6.02 Hz, 1H), 7.25 (dd,J=8.66, 2.64 Hz, 1H), 7.01-7.12 (m, 1H), 6.14-6.21 (m, 1H), 4.46 (t,J=8.53 Hz, 1H), 4.18-4.26 (m, 1H), 4.08-4.18 (m, 1H), 3.97-4.08 (m, 2H),3.82-3.93 (m, 1H), 3.53-3.67 (m, 3H), 3.34-3.40 (m, 1H), 3.08 (d,J=10.54 Hz, 2H), 2.46-2.60 (m, 1H), 2.28-2.44 (m, 1 H). MS: calc'd 506(MH⁺), measured 506 (MH⁺).

Example 5 Methyl(4R)-6-[[(8aS)-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared by SFC chiral separation of methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound F). Example 5 was obtained as a light yellow solid (14 mg). ¹HNMR (400 MHz, METHANOL-d₄) d ppm 7.90-7.99 (m, 1H), 7.72-7.82 (m, 1H),7.36-7.52 (m, 1H), 7.20-7.31 (m, 1H), 7.06 (td, J=8.41, 2.76 Hz, 1H),6.18 (s, 1H), 4.18 (d, J=17.07 Hz, 1H), 3.97-4.04 (m, 2H), 3.86-3.97 (m,1H), 3.61 (s, 3H), 3.21 (d, J=9.29 Hz, 1H), 3.03-3.16 (m, 1H), 2.83-2.95(m, 1H), 2.36-2.56 (m, 2H), 2.19-2.35 (m, 3H), 1.66-1.82 (m, 1 H). MS:calc'd 504 (MH⁺), measured 504 (MH⁺).

Preparation of methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound F)

Compound F was prepared in analogy to Example 1 by usinghexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (CAS number: 117810-52-3,Bepharm; for its synthesis, please refer to: Alvaro G., Large C. PCTInt. Appl., 2008090115) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D).

Example 6 Methyl(4R)-6-[[(8aR)-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared by SFC chiral separation of methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound F) in Example 5. Example 6 was obtained as a light yellowsolid (14 mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.87-8.01 (m, 1H),7.71-7.81 (m, 1H), 7.36-7.49 (m, 1H), 7.19-7.29 (m, 1H), 7.06 (td,J=8.41, 2.51 Hz, 1H), 6.18 (s, 1H), 4.11-4.21 (m, 1H), 4.06 (dd,J=12.55, 3.01 Hz, 1H), 3.95-4.02 (m, 1H), 3.89 (dtd, J=10.73, 7.25,7.25, 3.64 Hz, 1H), 3.53-3.65 (m, 3H), 3.01-3.19 (m, 3H), 2.33-2.54 (m,3H), 2.22 (dddd, J=13.08, 9.38, 7.65, 4.02 Hz, 1H), 2.12 (t, J=10.92 Hz,1H), 1.61-1.76 (m, 1 H). MS: calc'd 504 (MH⁺), measured 504 (MH⁺).

Example 7 Methyl(4R)-6-[[(8aR)-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 1 by using2-bromo-4-fluorobenzaldehyde and(8aR)-2,3,4,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-6-one (for itssynthesis, refer to: Tang P., et al, PCT Int. Appl., 2012019426) insteadof 2-chloro-4-fluorobenzaldehyde andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 7 wasobtained as a light yellow solid (19 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.95 (d, J=3.26 Hz, 1H), 7.76 (d, J=3.01 Hz, 1H), 7.35-7.48 (m,2H), 7.11 (td, J=8.41, 2.76 Hz, 1H), 6.17 (s, 1H), 4.09-4.19 (m, 1H),4.05 (dd, J=12.80, 2.76 Hz, 1H), 3.93-4.01 (m, 1H), 3.89 (dtd, J=10.63,7.23, 7.23, 3.76 Hz, 1H), 3.61 (s, 3H), 2.95-3.18 (m, 3H), 2.31-2.54 (m,3H), 2.15-2.28 (m, 1H), 2.08 (t, J=10.92 Hz, 1H), 1.61-1.75 (m, 1 H).MS: calc'd 548 (MH⁺), measured 548 (MH⁺).

Example 8 Ethyl(4R)-6-[[(8aR)-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl]methyl]-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 1 by using2-bromo-4-fluorobenzaldehyde, ethyl acetoacetate and(8aR)-2,3,4,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-6-one (for itssynthesis, refer to: Tang P., et al, PCT Int. Appl., 2012019426) insteadof 2-chloro-4-fluorobenzaldehyde, methyl acetoacetate andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 8 wasobtained as a light yellow solid (8 mg). ¹H NMR (400 MHz, METHANOL-d₄) dppm 7.95 (d, J=3.01 Hz, 1H), 7.76 (d, J=3.26 Hz, 1H), 7.36-7.53 (m, 2H),7.12 (td, J=8.34, 2.64 Hz, 1H), 6.18 (s, 1H), 4.11-4.17 (m, 1H), 4.05(q, J=6.86 Hz, 2H), 3.97 (d, J=16.81 Hz, 1H), 3.83-3.93 (m, 1H),2.94-3.19 (m, 3H), 2.30-2.53 (m, 3H), 2.22 (ddd, J=16.75, 12.86, 3.51Hz, 1H), 2.07 (t, J=10.67 Hz, 1H), 1.61-1.75 (m, 1H), 1.15 (t, J=7.15Hz, 3 H). MS: calc'd 562 (MH⁺), measured 562 (MH⁺).

Example 9 Ethyl(4S)-6-[[(8aR)-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl]methyl]-4-(3,4-difluorophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 1 by using3,4-difluorobenzaldehyde, ethyl acetoacetate and(8aR)-2,3,4,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-6-one (for itssynthesis, refer to: Tang P., et al, PCT Int. Appl., 2012019426) insteadof 2-chloro-4-fluorobenzaldehyde, methyl acetoacetate andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 9 wasobtained as a light yellow solid (11 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.94-8.05 (m, 1H), 7.81 (d, J=3.01 Hz, 1H), 7.14-7.33 (m, 3H),5.74 (s, 1H), 4.07-4.23 (m, 3H), 4.03 (dd, J=13.05, 2.51 Hz, 1H),3.83-3.94 (m, 2H), 3.09 (t, J=12.55 Hz, 1H), 2.98 (d, J=10.54 Hz, 2H),2.28-2.52 (m, 3H), 2.20 (ddt, J=17.00, 9.29, 3.80, 3.80 Hz, 1H), 2.05(t, J=10.92 Hz, 1H), 1.59-1.73 (m, 1H), 1.24 (t, J=7.15 Hz, 3 H). MS:calc'd 502 (MH⁺), measured 502 (MH⁺).

Example 10 Ethyl(4R)-4-(2-chloro-3-fluoro-phenyl)-6-[(6-oxo-3,4,7,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 1 by using2-chloro,3-fluorobenzaldehyde, ethyl acetoacetate and1,2,3,4,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-6-one hydrochloride salt(J & W Pharm Lab, CAS number: 151665-85-9; for its synthesis, pleaserefer to: Ghelardini C. et al. PCT Int. Appl., 2009103176) instead of2-chloro-4-fluorobenzaldehyde, methyl acetoacetate andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 10 wasobtained as a light yellow solid (6 mg). ¹H NMR (400 MHz, METHANOL-d₄) dppm 8.02 (d, J=3.26 Hz, 1 H), 7.96 (d, J=3.26 Hz, 1H), 7.23-7.38 (m,2H), 7.10-7.21 (m, 1H), 6.23 (s, 1 H), 4.56-4.78 (m, 2H), 3.82-4.21 (m,5H), 3.05-3.28 (m, 4H), 2.40 (m, 2H), 1.5-2.21 (m, 4 H), 1.21 (m, 3 H).MS: calc'd 532 (MH⁺), measured 532 (MH⁺).

Example 11 Methyl(4R)-6-[[(8aR)-3-oxo-1,2,5,6,8,8a-hexahydroimidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 1 by using(8aS)-2,5,6,7,8,8a-hexahydro-1H-imidazo[1,5-a]pyrazin-3-one (Compound H)instead of hexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D).Example 11 was obtained as a light yellow solid (11 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.93-8.01 (m, 1H), 7.72-7.81 (m, 1H), 7.38-7.49(m, 1H), 7.24 (dd, J=8.66, 2.64 Hz, 1H), 7.06 (td, J=8.47, 2.64 Hz, 1H),6.18 (s, 1H), 4.04-4.17 (m, 1H), 3.95-4.02 (m, 1H), 3.89-3.95 (m, 1H),3.84 (dd, J=13.43, 2.38 Hz, 1H), 3.61 (s, 3H), 3.53 (t, J=8.91 Hz, 1H),3.11-3.21 (m, 1H), 3.06 (dd, J=9.41, 4.64 Hz, 1H), 2.92 (dd, J=9.79,1.51 Hz, 1H), 2.84 (dd, J=11.17, 2.64 Hz, 1H), 2.38 (td, J=11.67, 3.51Hz, 1H), 2.19-2.29 (m, 1 H). MS: calc'd 505 (MH⁺), measured 505 (MH⁺).

Preparation of(8aS)-2,5,6,7,8,8a-hexahydro-1H-imidazo[1,5-a]pyrazin-3-one (Compound H)

Step 1: To a stirred solution of Na₂CO₃ (118 g, 1.11 mol) in water (600mL) was added (2S)-piperazine-2-carboxylic acid dihydrochloride salts(30 g, 0.15 mol) at 25° C., followed by di-tert-butyl dicarbonate (112g, 0.56 mol) and tetrahydrofuran (300 mL). Then the mixture was stirredfor additional 20 hours at room temperature. The reaction mixture wasconcentrated in vacuo and the resulting solution was extracted withmethyl tert-butyl ether (200 mL) three times to remove nonpolar species.The aqueous layer was cooled to below 0° C. and then treated with 3.0 MHCl until to pH 2 to 3. Then it was extracted with ethyl acetate (500mL) three times. The combined organic layer was dried over Na₂SO₄, andthen filtered and concentrated under vacuum to give Compound I (39 g).

Step 2: To a solution of Compound I (39 g, 0.12 mol) in tetrahydrofuran(200 mL) was added dropwise BH₃.THF complex (240 mL, 0.24 mol) at 0° C.under N₂ atmosphere. Then the mixture was warmed to room temperature andheated to reflux for 2˜3 hours. The mixture was quenched with MeOH (100mL) at 0° C. and the obtained solution was concentrated in vacuo. Theresidue was re-dissolved into MeOH (200 mL) and the solution wasrefluxed for 3 to 4 hours. Then the solvent was removed to give thecrude product (45 g). The crude product was purified by columnchromatography on silica (petroleum ether/EtOAc=10:1 to 1:1) to giveCompound J (31 g).

Step 3: To a solution of Compound J (15 g, 47.41 mmol), Ph₃P (16.17 g,61.63 mmol) and phthalimide (9.07 g, 61.63 mmol) in anhydroustetrahydrofuran (230 mL) was added a solution of diisopropylazodicarboxylate (12.46 g, 61.63 mmol) in tetrahydrofuran (20 mL) at 10°C. under N₂ atmosphere. Then the mixture was stirred for additional 2hours at 10° C. The mixture was quenched with 1N HCl (100 mL) and thenextracted with EtOAc (300 mL). The organic layer was dried over Na₂SO₄,filtered, and then concentrated in vacuo to give the crude product (50g). The crude product was triturated with petroleum ether/EtOAc (200 mL,V/V=5:1) to get crude product (25 g) with removal of triphenylphosphineoxide and other impurities. The crude product was purified by columnchromatography on silica (petroleum ether/EtOAc=20:1) to get the pureproduct K (12 g) as a white solid and some impure compound K (4 g).

Step 4: To a stirred solution of Compound K (12 g, 26.9 mmol) in ethanol(85 mL) was added methylamine alcohol solution (85 mL) at roomtemperature. Then the mixture was heated to reflux for additional 3hours. The mixture was cooled to room temperature and then concentrated.The resulting residue was dissolved in water (50 mL), then acidified topH 3 with 1N HCl solution, and then extracted with methyl-tert-butylether (50 mL) three times. The pH was adjusted to 10 with solid NaOH andthe mixture was extracted with ethyl acetate (150 mL) three times. Theorganic layer was dried and filtered and the solvent was removed underreduced pressure to give Compound L (6 g crude).

Step 5: To a stirred suspension of sodium hydride (1.0 g, 25 mmol) intetrahydrofuran (50 mL) was added Compound L (6 g, 19 mmol, crude) at 0°C. Then the mixture was heated to reflux for 2 hours. And thenadditional NaH (1.0 g, 25 mmol) was added into the mixture at roomtemperature. After the reaction mixture was refluxed for 1 hour, thereaction was quenched with ice-water (100 mL) and then extracted withEtOAc (300 mL). The organic layer was evaporated in vacuo to give thecrude product (5 g). The crude product was purified by columnchromatography on silica gel (EtOAc/MeOH=200:1) to give Compound M (2.2g, 40%).

Step 6: To a stirred solution of Compound M (2.2 g, 9.1 mmol) in 30 mLof dichloromethane was added dropwise 10 mL of TFA. After the reactionmixture was stirred for 1 hour, the solvent was removed in vacuo to give(8aS)-2,5,6,7,8,8a-hexahydro-1H-imidazo[1,5-a]pyrazin-3-one trifluoroacetitic acid salt (Compound H) as a crude product which was useddirectly without further purification.

Example 12 Methyl(4R)-6-[[(8aS)-3-oxo-1,2,5,6,8,8a-hexahydroimidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 11 by using(2R)-piperazine-2-carboxylic acid instead of(2S)-piperazine-2-carboxylic acid. Example 12 was obtained as a lightyellow solid (13 mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.91-8.01 (m,1H), 7.71-7.81 (m, 1H), 7.42 (dd, J=8.66, 6.15 Hz, 1H), 7.24 (dd,J=8.66, 2.64 Hz, 1H), 7.05 (td, J=8.41, 2.51 Hz, 1H), 6.18 (s, 1H), 4.12(d, J=17.32 Hz, 1H), 3.95-4.05 (m, 1H), 3.91 (d, J=17.32 Hz, 1H), 3.77(dd, J=13.18, 1.88 Hz, 1H), 3.61 (s, 3H), 3.56-3.60 (m, 1H), 3.08-3.21(m, 2H), 3.01 (dd, J=10.79, 2.76 Hz, 1H), 2.74 (d, J=11.29 Hz, 1H), 2.39(t, J=10.92 Hz, 1H), 2.24 (td, J=11.67, 3.26 Hz, 1 H). MS: calc'd 505(MH⁺), measured 505 (MH⁺).

Example 13 Ethyl(4R)-6-[[(8aS)-3-oxo-1,2,5,6,8,8a-hexahydroimidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 11 by using2-bromo-4-fluorobenzaldehyde and ethyl acetoacetate instead of2-chloro-4-fluorobenzaldehyde and methyl acetoacetate. Example 13 wasobtained as a light yellow solid (34 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.91-8.02 (m, 1H), 7.78 (d, J=3.01 Hz, 1H), 7.34-7.53 (m, 2H),7.12 (td, J=8.41, 2.76 Hz, 1H), 6.18 (s, 1H), 4.15-4.31 (m, 1H),3.93-4.13 (m, 4H), 3.76-3.89 (m, 1H), 3.61 (t, J=8.91 Hz, 1H), 3.07-3.25(m, 3H), 2.83-3.03 (m, 1H), 2.55 (br. s., 1H), 2.40 (br. s., 1H), 1.14(t, J=7.15 Hz, 3 H). MS: calc'd 563 (MH⁺), measured 563 (MH⁺).

Example 14 Ethyl(4R)-6-[[(8aR)-3-oxo-1,2,5,6,8,8a-hexahydroimidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 12 by using2-bromo-4-fluorobenzaldehyde and ethyl acetoacetate instead of2-chloro-4-fluorobenzaldehyde and methyl acetoacetate. Example 14 wasobtained as a light yellow solid (34 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.92-8.01 (m, 1H), 7.78 (d, J=3.26 Hz, 1H), 7.35-7.56 (m, 2H),7.12 (td, J=8.41, 2.76 Hz, 1H), 6.18 (s, 1H), 4.17-4.32 (m, 1H),3.96-4.16 (m, 4H), 3.89 (dd, J=13.55, 2.51 Hz, 1H), 3.49-3.64 (m, 1H),3.17-3.28 (m, 1H), 2.97-3.17 (m, 3H), 2.31-2.68 (m, 2H), 1.14 (t, J=7.15Hz, 3 H). MS: calc'd 563 (MH⁺), measured 563 (MH⁺).

Example 15 Methyl(4R)-6-[[(8aR)-1,3-dioxo-5,6,8,8a-tetrahydroimidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared by SFC chiral separation of methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(1,3-dioxo-5,6,8,8a-tetrahydroimidazo[1,5-a]pyrazin-7-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound N). Example 15 was obtained as a yellow solid (11 mg). ¹H NMR(400 MHz, METHANOL-d₄) d ppm 7.89-7.97 (m, 1H), 7.71-7.81 (m, 1H),7.38-7.53 (m, 1H), 7.24 (dd, J=8.78, 2.76 Hz, 1H), 7.07 (td, J=8.41,2.76 Hz, 1H), 6.19 (s, 1H), 4.28-4.40 (m, 1H), 4.15-4.26 (m, 1H),3.92-4.07 (m, 2H), 3.61 (s, 3H), 3.36 (d, J=4.77 Hz, 1H), 3.20-3.29 (m,1H), 2.78-2.86 (m, 1H), 2.42 (t, J=11.17 Hz, 1H), 2.29 (td, J=11.86,3.64 Hz, 1 H). MS: calc'd 519 (MH⁺), measured 519 (MH⁺).

Preparation of methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(1,3-dioxo-5,6,8,8a-tetrahydroimidazo[1,5-a]pyrazin-7-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound N)

The title compound was prepared in analogy to Example 1 by using6,7,8,8a-tetrahydro-5H-imidazo[1,5-a]pyrazine-1,3-dione (For itssynthesis, please refer to: WO2010/23480) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D).

Example 16 Methyl(4R)-6-[[(8aS)-1,3-dioxo-5,6,8,8a-tetrahydroimidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared by SFC chiral separation of methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(1,3-dioxo-5,6,8,8a-tetrahydroimidazo[1,5-a]pyrazin-7-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound N) in Example 15. Example 16 was obtained as a yellow solid(10 mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.90-7.97 (m, 1H), 7.76 (d,J=3.26 Hz, 1H), 7.37-7.49 (m, 1H), 7.24 (dd, J=8.78, 2.76 Hz, 1H), 7.06(td, J==8.41, 2.76 Hz, 1H), 6.19 (s, 1H), 4.24-4.36 (m, 1H), 4.13-4.22(m, 1H), 4.09 (dd, J=13.43, 2.89 Hz, 1H), 3.98-4.06 (m, 1H), 3.61 (s,3H), 3.27 (td, J=12.67, 3.76 Hz, 1H), 3.18 (dd, J=11.04, 4.27 Hz, 1H),2.97-3.04 (m, 1H), 2.44 (td, J=11.80, 3.76 Hz, 1H), 2.29 (t, J=11.17 Hz,1 H). MS: calc'd 519 (MH⁺), measured 519 (MH⁺).

Example 17 Methyl(4R)-6-[[(3aS)-1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazin-5-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared by SFC chiral separation of methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazin-5-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound O). Example 17 was obtained as a yellow solid (14 mg). ¹H NMR(400 MHz, METHANOL-d₄) d ppm 7.93-8.00 (m, 1H), 7.77 (d, J=3.01 Hz, 1H),7.44 (dd, J=8.78, 6.02 Hz, 1H), 7.25 (dd, J=8.66, 2.64 Hz, 1H), 7.06(td, J=8.41, 2.76 Hz, 1H), 6.18 (s, 1H), 4.12-4.26 (m, 1H), 3.97-4.10(m, 1H), 3.58-3.70 (m, 4H), 3.42-3.55 (m, 2H), 3.03-3.20 (m, 4H),2.63-2.76 (m, 1H), 2.42 (t, J=10.54 Hz, 1 H). MS: calc'd 541 (MH⁺),measured 541 (MH⁺).

Preparation of methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazin-5-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound O)

The title compound was prepared in analogy to Example 1 by usinghexahydro-1-thia-2,5,7a-triaza-indene 1,1-dioxide (Compound P) insteadof hexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D).

Preparation of hexahydro-1-thia-2,5,7a-triaza-indene 1,1-dioxide(Compound P)

To a stirred solution of 3-aminomethyl-piperazine-1-carboxylic acidtert-butyl ester (CAS number: 1376099-80-7, Bepharm) (215 mg, 1.0 mmol)in 2 mL of pyridine was added sulfamide (1.5 mmol). The reaction mixturewas heated to 150° C. for 6 hours under microwave. The solvent wasremoved in vacuo, and the residue was dissolved in 3 mL ofdichloromethane and 1 mL of TFA. The reaction mixture was stirred for 1hour, and the solvent was removed in vacuo to give the crude Compound Pwhich was used directly without further purification. LC/MS: calc'd 178(MH⁺), measured 178 (MH⁺).

Example 18 Methyl(4R)-6-[[(3aR)-1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazin-5-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared by SFC chiral separation of methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[(1,1-dioxo-2,3,3a,4,6,7-hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazin-5-yl)methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound O) in Example 17. Example 18 was obtained as a yellow solid(28 mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.97 (d, J=3.26 Hz, 1H),7.79 (d, J=3.26 Hz, 1H), 7.45 (dd, J=8.78, 6.02 Hz, 1H), 7.25 (dd,J=8.78, 2.51 Hz, 1H), 7.07 (td, J=8.41, 2.76 Hz, 1H), 6.19 (s, 1H), 4.32(d, J=16.81 Hz, 1H), 4.09 (d, J=16.81 Hz, 1H), 3.67-3.81 (m, 1H),3.58-3.66 (m, 3H), 3.46-3.58 (m, 2H), 3.29-3.31 (m, 1H), 3.23 (dd,J=9.79, 8.78 Hz, 1H), 3.02-3.19 (m, 2H), 2.69 (q, J=10.79 Hz, 2 H). MS:calc'd 541 (MH⁺), measured 541 (MH⁺).

Example 193-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid

The title compound was prepared in analogy to Example 1 by using2-chloro,3-fluorobenzaldehyde, ethyl acetoacetate and3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid (Compound Q) instead of 2-chloro-4-fluorobenzaldehyde, methylacetoacetate and hexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (CompoundD). Example 19 was obtained as a light yellow solid (12 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.92-8.02 (m, 1H), 7.70-7.80 (m, 1H), 7.21-7.36(m, 2H), 7.10-7.21 (m, 1H), 6.19-6.28 (m, 1H), 3.99-4.14 (m, 3H),3.81-3.96 (m, 3H), 3.47-3.56 (m, 1H), 3.38-3.44 (m, 1H), 3.27-3.32 (m,1H), 3.15-3.25 (m, 1H), 3.07-3.14 (m, 1H), 2.79-2.96 (m, 2H), 2.30-2.41(m, 1H), 2.13-2.23 (m, 1H), 1.20 (d, J=2.76 Hz, 6H), 1.13 (m, 3H). MS:calc'd 619 (MH⁺), measured 619 (MH⁺).

Preparation of3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid (Compound Q)

Step 1: To a stirred solution of (R)-4-N-boc-2-hydroxymethyl-piperazine(CAS number: 314741-40-7, Bepharm; for its synthesis, please refer to:Gao H., Renslo A. R. J. Org. Chem. 2007, 72, 8591-8592) (6 g, 27.8 mmol)in saturated NaHCO₃ (45 mL) and EtOAc (45 mL) was added benzylchloroformate (7.13 g, 41.7 mmol) dropwise at 0° C. Then the reactionmixture was stirred at room temperature for 15 hours. The reaction wasdiluted with EtOAc (60 mL), and the organic layer was separated andaqueous layer was extracted with EtOAc (35 mL). The combined organiclayer was dried over Na₂SO₄ and the solution was concentrated to give acrude product. The crude product was purified by column chromatographyon silica (Petroleum ether:EtOAc=10:1 to 1:1) to give Compound R (6.7g).

Step 2: To a stirred solution of oxalyl chloride (3.64 g, 28.65 mmol) inanhydrous dichloromethane (80 mL) at −78° C. was added dimethylsulfoxide (4.47 g, 57.3 mmol) dropwise. After 10 minutes, a solution ofCompound R (6.7 g, 19.1 mmol) in dichloromethane (20 mL) was addeddropwise. After the mixture was stirred for 30 minutes at −78° C.,N,N-diisopropylethylamine (14.78 g, 114.6 mmol) was added and thereaction mixture was stirred for 30 minutes. After the reaction mixturewas slowly warmed to 0° C. over 30 minutes, it was diluted withdichloromethane (80 mL), washed with 5% aqueous citric acid (10 mL),brine and then dried over Na₂SO₄. After filtration, the mixture wasconcentrated in vacuo to get the crude product S (7 g).

Step 3: To a stirred solution of ethyl 3-amino-2,2-dimethyl-propanoatehydrochloride salt (3.4 g, 18.6 mmol) in anhydrous DCM (100 mL) wasadded DIPEA (2.6 g, 27.3 mmol) at room temperature. Then Compound S (7g, 20 mmol) was added, followed by NaBH(OAc)₃ (6.3 g, 29.8 mmol) andAcOH (1.5 mL). The reaction mixture was stirred for 16 hours at roomtemperature. Water (100 mL) was added and the mixture was extracted withDCM (100 mL). The organic layer was dried and concentrated in vacuo todryness to give crude Compound T (7.3 g).

Step 4: To the solution of Compound T (3.3 g, 6.9 mmol) in EtOH (100 mL)was added Pd/C (1 g). Then the mixture was stirred at 50° C. for 3 hoursunder hydrogen atmosphere (50 Psi). The reaction mixture was filteredand the filtrate was concentrated in vacuo to get the Compound U (1.8g).

Step 5: To the solution of Compound U (1.8 g, 5.24 mmol) in anhydrousdichloromethane (60 mL) was added N,N-diisopropylethylamine (3.4 g, 26.2mmol) at 0° C. Then triphosgene (783 mg, 2.62 mmol) was added at 0° C.and the mixture was stirred at 10-15° C. for 16 hours. Water (50 mL) wasadded and the mixture was extracted with dichloromethane (60 mL), andthen dried over Na₂SO₄. The solvent was removed in vacuo to give thecrude product. The crude product was purified by column chromatographyon silica (petroleum ether:EtOAc=5:1 to 1:1) to obtain Compound V (1.3g).

Step 6: To a stirred solution of Compound V (240 mg, 0.64 mmol) in THF(3 ml) was added a solution of LiOH.H₂O (215 mg, 5.10 mmol) in H₂O (1mL) at room temperature. After the reaction mixture was stirred at roomtemperature overnight, it was acidified to PH 3 to 4 with 1 N HCl at 0°C. The mixture was then concentrated and azeotropically dried withtoluene to give the crude product which was dissolved in dichloromethane(2 mL) and treated with trifluoroacetic acid (2 mL) at room temperature.After the reaction mixture was stirred at room temperature for 1 hour,the solvent was removed in vacuo to give3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid (Compound Q) which was used directly.

Example 203-[(8aS)-7-[[(4R)-4-(2-chlorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2-methyl-propanoicacid

The title compound was prepared in analogy to Example 19 by using2-chlorobenzaldehyde and methyl 3-amino-2-methyl-propanoatehydrochloride salt (Compound W) instead of 2-chloro-4-fluorobenzaldehydeand ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt. Example 20was obtained as a light yellow solid (20 mg). ¹H NMR (400 MHz,METHANOL-d₄) d ppm 7.96 (d, J=3.01 Hz, 1H), 7.75 (d, J=3.01 Hz, 1H),7.42 (d, J=7.78 Hz, 2H), 7.14-7.36 (m, 2H), 6.22 (s, 1H), 3.97-4.16 (m,3H), 3.79-3.97 (m, 3H), 3.43-3.59 (m, 2H), 3.26-3.43 (m, 2H), 3.05-3.26(m, 2H), 2.80-2.99 (m, 2H), 2.65-2.80 (m, 1H), 2.35 (t, J=10.79 Hz, 1H),2.19 (q, J=10.46 Hz, 1H), 1.06-1.24 (m, 5 H). MS: calc'd 587 (MH⁺),measured 587 (MH⁺).

Preparation of methyl 3-amino-2-methyl-propanoate hydrochloride salt(Compound W)

To the solution of DL-3-aminoisobutyric acid (CAS number: 144-90-1,Aldrich) (2.7 g, 26.4 mmol) in MeOH (50 mL) was added SOCl₂ (6.17 g,52.8 mmol) dropwise at 0° C. under N₂ atmosphere. The reaction wasrefluxed for 18 hours. The solvent was removed in vacuo to give crudeCompound W which was used directly in the next step.

Example 213-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2-methyl-propanoicacid

The title compound was prepared in analogy to Example 19 by using methyl3-amino-2-methyl-propanoate hydrochloride salt (Compound W) instead ofethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt. Example 21 wasobtained as a light yellow solid (10 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.96 (d, J=3.26 Hz, 1H), 7.76 (d, J=3.26 Hz, 1H), 7.21-7.36 (m,2H), 7.10-7.21 (m, 1H), 6.24 (s, 1H), 3.98-4.17 (m, 3H), 3.79-3.98 (m,3H), 3.42-3.58 (m, 2H), 3.24-3.42 (m, 2H), 3.08-3.24 (m, 2H), 2.79-2.96(m, 2H), 2.73 (ddt, J=10.63, 7.00, 3.73, 3.73 Hz, 1H), 2.30-2.43 (m,1H), 2.13-2.27 (m, 1H), 1.08-1.24 (m, 5 H). MS: calc'd 605 (MH⁺),measured 605 (MH⁺).

Example 223-[(8aS)-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid

The title compound was prepared in analogy to Example 19 by using2-methyl-3,4-difluorobenzaldehyde instead of2-chloro-4-fluorobenzaldehyde. Example 22 was obtained as a light yellowsolid (2 mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.88-8.00 (m, 1H),7.69-7.80 (m, 1H), 6.95-7.13 (m, 2H), 5.88-5.99 (m, 1H), 4.03-4.16 (m,2H), 3.79-3.97 (m, 3H), 3.47-3.54 (m, 1H), 3.36-3.44 (m, 2H), 3.28-3.31(m, 1 H), 3.07-3.24 (m, 2H), 2.76-2.94 (m, 2H), 2.57 (d, J=2.26 Hz, 3H),2.31-2.42 (m, 1H), 2.12-2.22 (m, 1H), 1.10-1.24 (m, 9 H). MS: calc'd 617(MH⁺), measured 617 (MH⁺).

Example 23 Ethyl(4R)-4-(2-chloro-3-fluoro-phenyl)-6-[[2-(2-methoxyl-1,1-dimethyl-2-oxo-ethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

The title compound was prepared in analogy to Example 19 by using methyl3-amino-2-methyl-propanoate hydrochloride salt instead of ethyl3-amino-2,2-dimethyl-propanoate hydrochloride salt. Example 23 wasobtained as a light yellow solid (4 mg). ¹H NMR (400 MHz, METHANOL-d₄) dppm 7.94-8.03 (m, 1H), 7.72-7.82 (m, 1H), 7.22-7.38 (m, 2H), 7.11-7.20(m, 1H), 6.25 (s, 1H), 4.10-4.22 (m, 1H), 3.85-4.02 (m, 2H), 3.76-3.84(m, 1H), 3.74 (d, J=1.00 Hz, 2H), 3.59-3.71 (m, 1H), 3.12-3.30 (m, 2H),2.76-3.03 (m, 2H), 2.20-2.52 (m, 2H), 1.50 (t, J=7.78 Hz, 6H), 1.14 (t,J=7.03 Hz, 3 H). MS: calc'd 619 (MH⁺), measured 619 (MH⁺).

Example 24 Methyl7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-2,5,6,8-tetrahydro-1H-imidazo[1,5-a]pyrazine-8a-carboxylate

The title compound was prepared in analogy to Example 1 by using2-chloro,3-fluorobenzaldehyde, ethyl acetoacetate and methyl3-oxo-1,2,5,6,7,8-hexahydroimidazo[1,5-a]pyrazine-8a-carboxylate(Compound X) instead of 2-chloro-4-fluorobenzaldehyde, methylacetoacetate and hexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (CompoundD). Example 24 was obtained as a light yellow solid (5 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.96 (d, J=3.26 Hz, 1H), 7.76 (d, J=3.26 Hz,1H), 7.27-7.35 (m, 1H), 7.26 (s, 1H), 7.16 (s, 1H), 6.22 (s, 1H),3.97-4.14 (m, 3H), 3.87-3.95 (m, 1H), 3.78-3.85 (m, 1H), 3.67 (s, 3H),3.46 (d, J=9.79 Hz, 2H), 3.35-3.42 (m, 2H), 2.87-2.99 (m, 1H), 2.45-2.55(m, 1H), 2.29-2.42 (m, 1H), 1.12 (t, J=7.15 Hz, 3 H). MS: calc'd 577(MH⁺), measured 577 (MH⁺).

Preparation of methyl3-oxo-1,2,5,6,7,8-hexahydroimidazo[1,5-a]pyrazine-8a-carboxylate(Compound X)

Step 1: Piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methylester (244 mg, 1.0 mmol) was dissolved in 5 mL of dichloromethanefollowed by sequential addition of TEA (202 mg, 2.0 mmol) and benzylchloroformate (170 mg, 1.0 mmol) at room temperature. After the reactionwas stirred for 1 hour, it was diluted with dichloromethane, and thenwashed with water and brine. The solvent was concentrated to give crudeCompound Y, which was used directly without further purification.

Step 2: Piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butylester 2-methyl ester (Compound Y) from previous step was dissolved in 5mL of THF at −78° C., then LDA (2 M, 1 mL, 2 mmol) was added dropwise.After the reaction mixture was stirred for 2 hours at −78° C.,2-bromomethyl-isoindole-1,3-dione (239 mg, 1 mmol) in 2 mL of THF wasadded. The reaction mixture was stirred overnight. The solvent wasremoved in vacuo and the residue was triturate with petroleum ether. Thesolid was collected by filtration, washed with water and then dried invacuo to give Compound Z.

Step 3:2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-piperazine-1,2,4-tricarboxylicacid 1-benzyl ester 4-tert-butyl ester 2-methyl ester (Compound Z) fromStep 2 was dissolved in 3 mL of EtOH and 1 mL of N₂H₄ solution. Thereaction mixture was stirred at room temperature overnight. The solidwas filtered off and the filtrate was concentrated in vacuo. The crudeoil was dissolved in 10 mL of MeOH and stirred with 50 mg of Pd/C underH₂ atmosphere overnight. After filtration, the solvent was concentratedin vacuo to give 100 mg of crude Compound AA as oil, which was useddirectly without further purification in the next step.

Step 4: 3-Aminomethyl-piperazine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester (Compound AA) from Step 3 was dissolved in 4 mL ofdichloromethane and 1 mL of DIPEA, then triphosgene (108 mg, 0.36 mmol)was added at room temperature. After the reaction mixture was stirredfor 30 minutes, the solvent was removed in vacuo. The residue wasdissolved in 3 mL of dichloromethane and 1 mL of TFA. The reactionmixture was stirred for 1 hour at room temperature, and the solvent wasremoved in vacuo to give the crude Compound X which was used directlywithout further purification.

Example 25(R)-6-[(S)-2-(4-Carboxy-phenyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1 by using4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]benzoicacid (Compound AB) instead of hexahydro-pyrazino[1,2-c][1,3]oxazin-6-one(Compound D). Example 25 was obtained as a light yellow solid (45 mg).¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.93-8.06 (m, 3H), 7.79 (d, 1H),7.64-7.75 (m, 2H), 7.45 (m, 1H), 7.25 (m, 1H), 7.08 (m, 1H), 6.19 (s,1H), 4.22 (d, 1H), 3.95-4.15 (m, 4H), 3.53-3.66 (m, 4H), 3.29 (d, 1H),3.09 (d, 2H), 3.03-3.17 (m, 2H), 2.50-2.63 (m, 1H), 2.35 (br. s., 1H).MS: calc'd 625 (MH⁺), measured 625 (MH⁺).

Preparation of4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]benzoicacid (Compound AB)

Step 1: A mixture of tert-butyl(8aR)-3-oxo-1,2,5,6,8,8a-hexahydroimidazo[1,5-a]pyrazine-7-carboxylate(Compound M, 200 mg, 0.83 mmol), xantphos (46 mg, 0.08 mmol), Cs₂CO₃(378 mg, 1.16 mmol), Pd(OAc)₂ (18 mg, 0.08 mmol) and 4-iodo-benzoic acidmethyl ester (282 mg, 1.08 mmol) in dioxane (6 mL) was degassed withargon atmosphere three times. The mixture was stirred at roomtemperature for 5 minutes under argon atmosphere, and then heated at 90°C. overnight. The mixture was diluted with EtOAc (20 mL), and filteredthrough celite. The filtrate was concentrated and purified on silica gelto give Compound AC (240 mg).

Step 2: To a solution of Compound AC (240 mg, 0.64 mmol) in THF (3 mL)was added a solution of LiOH.H₂O (215 mg, 5.10 mmol) in H₂O (1 mL) atroom temperature. After the reaction mixture was stirred at roomtemperature overnight, it was acidified to PH 3 to 4 with 1 N HCl at 0°C. The mixture was then concentrated and azeotropically dried withtoluene to give Compound AD (231 mg) which was used directly withoutfurther purification in the next step.

Step 3: To a solution of Compound AD (231 mg, 0.64 mmol) indichloromethane (2 mL) was added TFA (2 mL) at room temperature. Themixture was stirred at room temperature for 1 hour, then concentrated togive methyl4-(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)benzoic acid(Compound AB) (240 mg).

Example 26(R)-6-[(S)-2-(4-Carboxy-phenyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

The title compound was prepared in analogy to Example 25 by using2-chloro,3-fluorobenzaldehyde and ethyl acetoacetate instead of2-chloro-4-fluorobenzaldehyde and methyl acetoacetate. Example 26 wasobtained as a light yellow solid (76 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.85-7.96 (m, 3H), 7.79 (d, 1H), 7.61 (d, 2H), 7.23-7.30 (m, 2H),7.08-7.19 (m, 1H), 6.16 (s, 1H), 4.62 (d, 1H), 4.43 (d, 1H), 4.22 (m,1H), 4.02-4.16 (m, 2H), 3.97 (m, 2H), 3.57-3.73 (m, 3H), 3.36-3.49 (m,1H), 3.02-3.16 (m, 2H), 0.95-1.08 (m, 3H). MS: calc'd 639 (MH⁺),measured 639 (MH⁺).

Example 27(R)-6-[(S)-2-(3-Carboxy-phenyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

The title compound was prepared in analogy to Example 25 by using2-chloro,3-fluorobenzaldehyde, ethyl acetoacetate and3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]benzoicacid (Compound AE) instead of 2-chloro-4-fluorobenzaldehyde, methylacetoacetate and4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]benzoicacid (Compound AB). Example 27 was obtained as a light yellow solid (20mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 8.11 (s, 1H), 7.90 (d, 1H),7.75-7.82 (m, 2H), 7.66 (d, 1H), 7.37 (m, 1H), 7.23-7.29 (m, 2H),7.07-7.17 (m, 1H), 6.16 (s, 1H), 4.59 (d, 1H), 4.34-4.45 (m, 1H),4.15-4.25 (m, 1H), 4.01-4.13 (m, 2H), 3.97 (m, 2H), 3.52-3.67 (m, 3H),3.36-3.46 (m, 1H), 3.02-3.16 (m, 2H), 1.01 (m, 3H). MS: calc'd 639(MH⁺), measured 639 (MH⁺).

Preparation of3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]benzoicacid (Compound AE)

Compound AE was prepared in analogy to Compound AB in Example 25 byusing 3-iodo-benzoic acid methyl ester instead of 4-iodo-benzoic acidmethyl ester.

Example 28(R)-6-[(S)-2-(2-Carboxy-phenyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

The title compound was prepared in analogy to Example 25 by using2-chloro,3-fluorobenzaldehyde and ethyl acetoacetate and2-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]benzoicacid (Compound AF) instead of 2-chloro-4-fluorobenzaldehyde and methylacetoacetate and4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]benzoicacid (Compound AB). Example 28 was obtained as a light yellow solid (95mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.83-7.93 (m, 2H), 7.80 (d,1H), 7.53 (m, 1H), 7.24-7.35 (m, 4H), 7.08-7.19 (m, 1H), 6.16 (s, 1H),4.66 (d, 1H), 4.48 (d, 1H), 4.20-4.29 (m, 1H), 4.06-4.11 (m, 1H),3.92-4.04 (m, 3H), 3.65 (d, 2H), 3.29-3.55 (m, 3H), 3.13 (m, 1H), 1.02(m, 3H). MS: calc'd 639 (MH⁺), measured 639 (MH⁺).

Preparation of2-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]benzoicacid (Compound AF)

The title compound was prepared in analogy to Compound AB in Example 25by using 2-iodo-benzoic acid methyl ester instead of 4-iodo-benzoic acidmethyl ester.

Example 29(R)-6-[(S)-2-(3-Carboxy-phenyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 25 by using3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]benzoicacid (Compound AE) instead of4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]benzoicacid (Compound AB). Example 29 was obtained as a light yellow solid (220mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 8.20-8.26 (m, 1H), 8.03 (d,1H), 7.85-7.96 (m, 2H), 7.78 (m, 1H), 7.56 (m, 1H), 7.49 (m, 1H), 7.30(m, 1H), 7.13 (m, 1H), 6.21 (s, 1H), 4.78 (d, 1H), 4.55-4.63 (m, 1H),4.36 (dm, 1H), 4.13-4.29 (m, 2H), 3.72-3.90 (m, 3H), 3.65 (s, 3H),3.51-3.61 (m, 1H), 3.35-3.40 (m, 1H), 3.26-3.31 (m, 1H). MS: calc'd 625(MH⁺), measured 625 (MH⁺).

Example 302-[7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-cyclopropyl-3-oxo-1,5,6,8-tetrahydroimidazo[1,5-a]pyrazin-8a-yl]aceticacid

The title compound was prepared in analogy to Example 1 by using4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]benzoicacid (Compound AG) instead of hexahydro-pyrazino[1,2-c][1,3]oxazin-6-one(Compound D). Example 30 was obtained as a light yellow solid (48 mg).¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.93 (d, J=3.0 Hz, 1H), 7.73 (d,J=3.0 Hz, 1H), 7.43 (dd, J=6.1, 8.7 Hz, 1H), 7.24 (dd, J=2.5, 8.8 Hz,1H), 7.06 (d, J=2.8 Hz, 1H), 6.16 (s, 1H), 4.14 (d, J=16.6 Hz, 1H),3.85-3.71 (m, 2H), 3.60 (s, 3H), 3.46 (d, J=9.8 Hz, 1H), 3.30-3.15 (m,3H), 3.06 (d, J=11.3 Hz, 1H), 2.95-2.82 (m, 2H), 2.45 (d, J=5.0 Hz, 1H),2.39-2.29 (m, 1H), 2.22 (d, J=11.5 Hz, 1H), 0.83-0.53 (m, 4H). MS:calc'd 604 (MH⁺), measured 604 (MH⁺).

Preparation of4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]benzoicacid (Compound AG)

Step 1: To a solution of piperazine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester (10.6 g, 43 mmol) in 250 mL of dichloromethane wasadded (Boc)₂O (19 g, 86 mmol) at 0° C. The reaction mixture stirred for4 hours at room temperature, and then quenched with water and thenextracted with dichloromethane. After the organic layer was dried overanhydrous Na₂SO₄, the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give Compound AH (yield13.6 g, 92%).

Step 2: To a solution of Compound AH (13.4 g, 38.9 mmol) in 200 mL ofanhydrous THF was added freshly prepared LDA (2M in THF, 38 mL) at −78°C. The reaction mixture was stirred for 30 minutes at −78° C. and thenwarmed to room temperature for 30 minutes. The mixture was cooled downto −78° C. and a solution of allyl bromide (6.7 mL, 77.9 mmol) in 10 mLof THF was added. After the mixture was warmed to room temperature andstirred overnight, the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography to affordCompound AI (yield 13.6 g, 91%).

Step 3: To a solution of Compound AI (1.0 g, 2.6 mmol) in 20 mL ofanhydrous THF was added LAH (2M in THF, 1.3 mL) at −78° C. The reactionmixture was stirred for 30 minutes at −78° C. and then warmed to roomtemperature and stirred overnight. Anhydrous Na₂SO₄ was added.

After 1 hour, the filtrate was concentrated. The residue was purified bysilica gel column chromatography to afford Compound AJ (yield 0.7 g,75%).

Step 4: To a solution of Compound AJ (3 g, 8.4 mmol) in 50 mL ofanhydrous dichloromethane was added Dess-Martin periodinane (6 g, 14.1mmol) at 0° C. The reaction mixture was stirred for 2 hours at roomtemperature, and then quenched with water. The filtrate was extractedwith dichloromethane, and then dried over anhydrous Na₂SO₄, and thefiltrate was concentrated to give Compound AK without furtherpurification.

Step 5: To a stirred solution of Compound AK (1.5 g, 4.2 mmol) indichloromethane (15 mL) was added successively acetic acid andcyclopropylamine (0.29 mL, 4.2 mmol). The reaction mixture was stirredfor 2 hours at room temperature, then sodium triacetoxyborohydride (520mg, 8.4 mmol) was added and the reaction mixture was stirred for 3 hoursat room temperature. The reaction mixture was quenched with saturatedNH₄Cl. Then water (20 mL) was added followed by dichloromethane (40 mL).The organic layer was separated and then washed with brine, and thendried over Na₂SO₄. The filtrate was concentrated to give Compound ALwithout further purification.

Step 6: To a solution of Compound AL (1.5 g, 3.8 mmol) in 20 mL ofanhydrous THF was added NaH (0.26 g, 9.4 mmol) at 0° C. The reactionmixture was stirred over night at 85° C. Then the reaction was cooled toroom temperature, quenched with water and extracted withdichloromethane. The organic layer was dried over anhydrous Na₂SO₄ andthen concentrated in vacuo. The residue was purified by silica gelcolumn chromatography to give Compound AM (yield 1.0 g, 82%).

Step 7: To a solution of Compound AM (700 mg, 2.2 mmol) in H₂O (1 mL)and CH₃CN (6 mL) under nitrogen atmosphere was added RuCl₃.H₂O (18 mg,0.086 mmol), followed by NaIO₄ (2.7 g, 12.6 mmol). The reaction wasstirred at room temperature overnight. The mixture was diluted withwater and ethyl ether, filtered through a celite pad, and the pad waswashed with ethyl ether. The aqueous layer was extracted withdichloromethane. The combined organic layers were dried over Na₂SO₄, andconcentrated to give Compound AN (yield 450 mg, 60%).

Step 8: To a solution of Compound AN (600 mg, 1.76 mmol) indichloromethane (8 mL) was added TFA (2 mL) at 0° C. After the reactionmixture was stirred for 2 hours at room temperature, it was concentratedto give Compound AG without further purification.

Example 312-[7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isopropyl-3-oxo-1,5,6,8-tetrahydroimidazo[1,5-a]pyrazin-8a-yl]aceticacid

The title compound was prepared in analogy to Example 30 by using2-(2-isopropyl-3-oxo-5,6,7,8-tetrahydro-1H-imidazo[1,5-a]pyrazin-8a-yl)aceticacid (Compound AO) instead of4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]benzoicacid (Compound AG). Example 31 was obtained as a light yellow solid (8mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.94 (d, J=3.0 Hz, 1H), 7.73(d, J=3.3 Hz, 1H), 7.43 (dd, J=6.0, 8.8 Hz, 1H), 7.24 (dd, J=2.8, 8.8Hz, 1H), 7.11-7.02 (m, 1H), 6.16 (s, 1H), 4.18-4.04 (m, 2H), 3.79 (d,J=16.6 Hz, 2H), 3.61 (s, 3H), 3.47 (d, J=9.5 Hz, 1H), 3.29-3.24 (m, 1H),3.20 (d, J=9.5 Hz, 1H), 3.09 (d, J=11.5 Hz, 1H), 2.90 (d, J=15.6 Hz,2H), 2.38-2.12 (m, 3H), 1.18 (d, J=7.0 Hz, 3H), 1.12 (d, J=6.8 Hz, 3H).MS: calc'd 606 (MH⁺), measured 606 (MH⁺).

Preparation of2-(2-isopropyl-3-oxo-5,6,7,8-tetrahydro-1H-imidazo[1,5-a]pyrazin-8a-yl)aceticacid (Compound AO)

The title compound was prepared in analogy to Compound AG in Example 30by using iso-propyl amine instead of cyclopropyl amine.

Example 32(R)-6-[(S)-2-(1-Carboxyl-1-methyl-ethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

The title compound was prepared in analogy to Example 19 by using methyl2-amino-2-methyl-propanoate hydrochloride salt instead of ethyl3-amino-2,2-dimethyl-propanoate hydrochloride salt. Example 32 wasobtained as a light yellow solid (60 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.98 (d, 1H), 7.79 (d, 1H), 7.23-7.38 (m, 2H), 7.09-7.23 (m, 1H),6.25 (s, 1H), 4.23 (br. s., 1H), 4.06 (m, 3H), 3.78-3.97 (m, 2H),3.59-3.71 (m, 1H), 3.14-3.29 (m, 2H), 2.89-3.14 (m, 2H), 2.54 (br. s.,2H), 1.40-1.57 (m, 6H), 1.04-1.19 (m, 3H). MS: calc'd 605 (MH⁺),measured 605 (MH⁺).

Example 333-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-3-methyl-butanoicacid

The title compound was prepared in analogy to Example 19 by using2-chloro-4-fluorobenzaldehyde, methyl acetoacetate and3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-3-methyl-butanoicacid (Compound AP) instead of 2-chloro-3-fluorobenzaldehyde, ethylacetoacetate and3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid (Compound Q). Example 33 was obtained as a light yellow solid (381mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 8.00-8.01 (d, J=4.0Hz, 1H),7.90-7.91 (d, J=4.0Hz, 1H), 7.55 (m, 1H), 7.29 (m, 1H), 7.13 (m, 1H),6.20 (s, 1H), 4.76 (d, J=16.0 Hz, 1H), 4.60 (d, J=16.0 Hz, 1H), 4.12 (m,1H), 4.02-4.06 (m, 1H), 3.70-3.80 (m, 3H), 3.65 (s, 3H), 3.32-3.44 (m,2H), 3.20 (m, 2H), 3.09-3.05 (d, J=16.0Hz, 1H), 2.79-2.83 (d, J=16.0Hz,1H), 1.47 (s, 6H). MS: calc'd 605 (MH⁺), measured 605 (MH⁺).

Preparation of3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-3-methyl-butanoicacid (Compound AP)

The title compound was prepared in analogy to Compound Q in Example 19by using methyl 3-amino-3-methyl-butanoate hydrochloride salt (CompoundAP-1) instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloridesalt.

Preparation of methyl 3-amino-3-methyl-butanoate hydrochloride salt(Compound AP-1)

Compound AP-1 was prepared in analogy to Compound W in Example 20 byusing 3-amino-3-methyl-butyric acid instead of DL-3-aminoisobutyricacid.

Example 343-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-3-methyl-butanoicacid

The title compound was prepared in analogy to Example 19 by using3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-3-methyl-butanoicacid (Compound AP) instead of3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid (Compound Q). Example 34 was obtained as a light yellow solid (26mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.99-8.00 (d, J=4.0Hz, 1H),7.83-7.84 (d, J=4.0Hz, 1H), 7.35 (m, 2H), 7.20 (m, 1H), 6.25 (s, 1H),4.20-4.40 (m, 2H), 4.10 (m, 2H), 3.94 (m, 2H), 3.70 (m, 2H), 3.29 (m,5H), 3.02-3.06 (d, J=16.0Hz, 1H), 2.80-2.84 (d, J=16.0Hz, 1H), 1.46 (s,6H), 1.11-1.15 (t, J₁=8.0Hz, J₂=16.0Hz, 3H). MS: calc'd 619 (MH⁺),measured 619 (MH⁺).

Example 351-[[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]methyl]cyclopropanecarboxylicacid

The title compound was prepared in analogy to Example 19 by using2-chloro-4-fluorobenzaldehyde, methyl acetoacetate and methyl1-(aminomethyl)cyclopropanecarboxylate hydrochloride salt (Compound AQ)instead of 2-chloro,3-fluorobenzaldehyde, ethyl acetoacetate and ethyl3-amino-2,2-dimethyl-propanoate hydrochloride salt. Example 35 wasobtained as a light yellow solid (760 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 8.00-8.01 (d, J=4.0Hz, 1H), 7.90-7.91 (d, J=4.0Hz, 1H), 7.55 (m,1H), 7.29 (m, 1H), 7.13 (m, 1H), 6.20 (s, 1H), 4.77 (d, J=16.0 Hz, 1H),4.59 (d, J=16.0 Hz, 1H), 4.19 (m, 1H), 4.07-4.10 (m, 1H), 3.73-3.77 (m,3H), 3.65 (s, 3H), 3.36-3.50 (m, 4H), 3.15-3.24 (m, 2 H), 1.29 (m, 2H),1.02 (m, 2H). MS: calc'd 603 (MH⁺), measured 603 (MH⁺).

Preparation of methyl 1-(aminomethyl)cyclopropanecarboxylatehydrochloride salt (Compound AQ)

The title compound was prepared in analogy to Compound W in Example 20by using 1-(aminomethyl)cyclopropanecarboxylic acid (CAS number:139132-50-6, J&K; for its synthesis, please refer to: Mertin A., et al.Synlett, 1991, 2, 87-9) instead of DL-3-aminoisobutyric acid.

Example 361-[[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]methyl]cyclopropanecarboxylicacid

The title compound was prepared in analogy to Example 19 by using methyl1-(aminomethyl)cyclopropanecarboxylate hydrochloride salt (Compound AQ)instead ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt.Example 36 was obtained as a light yellow solid (170 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 8.00-8.01 (d, J=4.0Hz, 1H), 7.92-7.91 (d,J=4.0Hz, 1H), 7.38 (m, 2H), 7.26 (m, 1H), 6.27 (s, 1H), 4.77 (d, J=16.0Hz, 1H), 4.59 (d, J=16.0 Hz, 1H), 4.11 (m, 1H), 4.07-4.10 (m, 3H),3.72-3.78 (m, 3H), 3.36-3.47 (m, 4H), 3.15-3.24 (m, 2 H), 1.29 (m, 2H),1.13 (t, J₁=8.0Hz, J₂=16.0Hz, 3H), 1.02 (m, 2H). MS: calc'd 617 (MH⁺),measured 617 (MH⁺).

Example 371-[[(8aS)-7-[[(4S)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]methyl]cyclopropanecarboxylicacid

The title compound was prepared in analogy to Example 19 by using2-methyl-3,4-difluorobenzaldehyde, methyl acetoacetate and3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-3-methyl-butanoicacid (Compound AP) instead of 2-chloro-3-fluorobenzaldehyde, ethylacetoacetate and3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid (Compound Q). Example 37 was obtained as a light yellow solid (153mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 8.00-8.01 (d, J=4.0Hz, 1H),7.90-7.91 (d, J=4.0Hz, 1H), 7.26 (m, 1H), 7.10 (m, 1H), 5.95 (s, 1H),4.74 (d, J=16.0 Hz, 1H), 4.57 (d, J=16.0 Hz, 1H), 4.10 (m, 2H),3.70-3.80 (m, 3H), 3.66 (s, 3H), 3.36-3.42 (m, 2H), 3.20 (m, 2H),3.09-3.05 (d, J=16.0Hz, 1H), 2.79-2.83 (d, J=16.0Hz, 1H), 2.53 (s, 3H),1.47 (s, 6H). MS: calc'd 603 (MH⁺), measured 603 (MH⁺).

Example 381-[[(8aS)-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]methyl]cyclopropanecarboxylicacid

The title compound was prepared in analogy to Example 35 by using2-methyl-3,4-difluorobenzaldehyde instead of2-chloro-4-fluorobenzaldehyde. Example 38 was obtained as a light yellowsolid (54 mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 8.00-8.01 (d,J=4.0Hz, 1H), 7.90-7.91 (d, J=4.0Hz, 1H), 7.26 (m, 1H), 7.12 (m, 1H),5.95 (s, 1H), 4.74 (d, J=16.0 Hz, 1H), 4.56 (d, J=16.0 Hz, 1H),4.07-4.17 (m, 2H), 3.70-3.77 (m, 3H), 3.66 (s, 3H), 3.35-3.46 (m, 4H),3.15-3.22 (m, 2H), 2.51 (s, 3H), 1.29 (m, 2H), 1.02 (m, 2H). MS: calc'd601 (MH⁺), measured 601 (MH⁺).

Example 393-[(2S,8aR)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclobutanecarboxylicacid

The title compound was prepared in analogy to Example 19 by using2-chloro-4-fluorobenzaldehyde, methyl acetoacetate and methyltrans-3-amino-cyclobutanecarboxylate hydrochloride (CAS number:74316-29-3; for its synthesis, please refer to: Grygorenko O. O., et al.Synthetic Communications, 2011, 41, 1644-1649) instead of2-chloro-3-fluorobenzaldehyde, ethyl acetoacetate and ethyl3-amino-2,2-dimethyl-propanoate hydrochloride. Example 39 was obtainedas a light yellow solid (44 mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm7.97 (dd, J=4.0, 3.3 Hz, 1H), 7.77 (dd, J=3.1, 1.4 Hz, 1H), 7.43 (ddd,J=8.7, 6.1, 2.5 Hz, 1H), 7.20-7.28 (m, 1H), 6.99-7.13 (m, 1H), 6.18 (s,1H), 4.58-4.73 (m, 1H), 4.11 (dd, J=16.9, 4.6 Hz, 1H), 3.73-3.97 (m,3H), 3.61 (s, 3H), 2.82-3.28 (m, 5H), 2.74 (d, J=11.8 Hz, 1H), 2.15-2.65ppm (m, 6H). MS: calc'd 603 (MH⁺), measured 603 (MH⁺).

Example 403-[(8aR)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclobutanecarboxylicacid

The title compound was prepared in analogy to Example 19 by using2-chloro-4-fluorobenzaldehyde, methyl acetoacetate and methylcis-3-amino-cyclobutanecarboxylate hydrochloride (CAS number:1212304-86-3; for its synthesis, please refer to: Grygorenko O. O., etal. Synthetic Communications, 2011, 41, 1644-1649) instead of2-chloro-3-fluorobenzaldehyde, ethyl acetoacetate and ethyl3-amino-2,2-dimethyl-propanoate hydrochloride. Example 40 was obtainedas a light yellow solid (5 mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm7.92-8.02 (m, 1H), 7.77 (dd, J=3.1, 1.4 Hz, 1H), 7.38-7.48 (m, 1H), 7.24(d, J=6.3 Hz, 1H), 6.98-7.15 (m, 1H), 6.18 (s, 1H), 4.58-4.75 (m, 1H),4.04-4.19 (m, 1H), 3.72-3.97 (m, 3H), 3.61 (s, 4H), 2.81-3.27 (m, 6H),2.33-2.63 ppm (m, 5H). MS: calc'd 603 (MH⁺), measured 603 (MH⁺).

Example 413-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid

The title compound was prepared in analogy to Example 19 by using methylacetoacetate instead of ethyl acetoacetate. Example 41 was obtained as alight yellow solid (250 mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.97(d, J=3.3 Hz, 1H), 7.76 (d, J=3.0 Hz, 1H), 7.09-7.36 (m, 3H), 6.23 (s,1H), 4.04-4.15 (m, 1H), 3.78-3.98 (m, 3H), 3.61 (s, 3H), 3.36-3.55 (m,3H), 3.04-3.28 (m, 2H), 2.76-2.99 (m, 2H), 2.12-2.45 (m, 2H), 1.15-1.25ppm (m, 6H). MS: calc'd 605 (MH⁺), measured 605 (MH⁺).

Example 423-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid

The title compound was prepared in analogy to Example 19 by using2-chloro-4-fluorobenzaldehyde and methyl acetoacetate instead of2-chloro-3-fluorobenzaldehyde and ethyl acetoacetate. Example 42 wasobtained as a light yellow solid (260 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.97 (d, J=3.0 Hz, 1H), 7.76 (d, J=3.3 Hz, 1H), 7.42 (dd, J=8.5,6.0 Hz, 1H), 7.24 (dd, J=8.7, 2.6 Hz, 1H), 7.06 (td, J=8.4, 2.8 Hz, 1H),6.17 (s, 1H), 4.09 (d, J=16.8 Hz, 1H), 3.79-3.98 (m, 3H), 3.61 (s, 3H),3.51 (t, J=8.9 Hz, 1H), 3.36-3.44 (m, 1H), 3.04-3.26 (m, 3H), 2.75-3.00(m, 2H), 2.11-2.43 (m, 2H), 1.20 ppm (d, J=3.0 Hz, 6H). MS: calc'd 605(MH⁺), measured 605 (MH⁺).

Example 433-[(8aS)-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid

The title compound was prepared in analogy to Example 19 by using2-methyl-3,4-difluorobenzaldehyde and methyl acetoacetate instead of2-chloro-3-fluorobenzaldehyde and ethyl acetoacetate. Example 43 wasobtained as a light yellow solid (110 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.95 (d, J=3.3 Hz, 1H), 7.75 (d, J=3.3 Hz, 1H), 6.96-7.09 (m, 2H),5.93 (s, 1H), 4.04-4.16 (m, 1H), 3.78-3.98 (m, 3H), 3.62 (s, 3H),3.36-3.56 (m, 3H), 3.05-3.26 (m, 2H), 2.74-2.97 (m, 2H), 2.57 (d, J=2.3Hz, 3H), 2.36 (td, J=11.7, 3.6 Hz, 1H), 2.18 (t, J=10.9 Hz, 1H), 1.20ppm (d, J=3.3 Hz, 6H). MS: calc'd 603 (MH⁺), measured 603 (MH⁺).

Example 443-[(8aS)-7-[[(4S)-4-(3-fluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid

The title compound was prepared in analogy to Example 19 by using2-methyl-3-fluorobenzaldehyde and methyl acetoacetate instead of2-chloro-3-fluorobenzaldehyde and ethyl acetoacetate. Example 44 wasobtained as a light yellow solid (74 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.95 (d, J=3.0 Hz, 1H), 7.74 (d, J=3.3 Hz, 1H), 7.03-7.21 (m, 2H),6.88-6.99 (m, 1H), 5.98 (s, 1H), 4.03-4.17 (m, 1H), 3.79-3.99 (m, 4H),3.62 (s, 3H), 3.41-3.56 (m, 2H), 3.07-3.26 (m, 2H), 2.75-2.98 (m, 2H),2.53 (d, J=2.0 Hz, 3H), 2.29-2.45 (m, 1H), 2.18 (t, J=11.2 Hz, 1H), 1.20ppm (d, J=3.3 Hz, 6H). MS: calc'd 585 (MH⁺), measured 585 (MH⁺).

Example 457-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid

Preparation of Example 45

The solution of methyl7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylate(Compound AQ, 150 mg, 0.25 mmol) in tetrahydrofuran (1.5 mL) was addedlithium hydroxide monohydrate (52 mg, 1.25 mmol) in water (1.5 mL).After the reaction mixture was stirred at room temperature for 2 hours,it was neutralized by 1N hydrochloride solution to pH 3.0. The mixturewas extracted with ethyl acetate (30 mL) three times. The combinedorganic phase was dried over Na₂SO₄, filtrated and then concentrated.The residue was purified by Prep-HPLC to give Example 45 as a mixture oftwo diastereomers (5 mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 8.06-7.95(m, 1H), 7.87 (s, 1H), 7.55-7.44 (m, 1H), 7.32-7.23 (m, 1H), 7.15-7.03(m, 1H), 6.18 (s, 1H), 4.37-4.21 (m, 1H), 4.09-3.91 (m, 1H), 3.91-3.77(m, 2H), 3.62 (d, J=2.0 Hz, 4H), 3.52-3.39 (m, 2H), 3.22-2.96 (m, 2H),2.75-2.58 (m, 1H), 2.50-2.42 (m, 1H), 0.74 (d, J=1.5 Hz, 4H). MS: calc'd589 (MH⁺), measured 589 (MH⁺).

Preparation of7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylate(Compound AQ)

The title compound was prepared in analogy to Example 1 by using methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(Compound AR) instead of hexahydro-pyrazino[1,2-c][1,3]oxazin-6-one(Compound D).

Preparation of cis-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(Compound AR)

Step 1: To a solution of dimethyl maleate (7.2 g, 50 mmol) intetrachloromethane (150 mL) was added dropwise bromine (8.8 g, 55 mmol)in tetrachloromethane (10 mL) at 0° C. under nitrogen atmosphere. Thereaction mixture was stirred at 0° C. overnight. The reaction mixturewas quenched by adding ice-water, and then washed with Na₂SO₃ solution.The organic phase was washed with water, separated, dried over Na₂SO₄and then concentrated to give crude Compound AS (15.2 g, crude).

Step 2: To a solution of Compound AS (10.6 g, 35 mmol) in benzene (120mL) was added dropwise N,N-dibenzylethylenediamine (8.4 g, 35 mmol) andtriethyl amine (9.7, 70 mmol) in benzene (20 mL) at 40° C. undernitrogen atmosphere. The reaction mixture was stirred for 10 minutes andheated to reflux overnight. The reaction mixture was cooled down byadding ice-water, and then extracted with petroleum ether/ethylacetate=10/1 (50 mL) three times, the combined organic phase was driedover Na₂SO₄, filtrated and then concentrated. The residue was purifiedby column chromatography to give Compound AT (3.3 g).

Step 3: To a solution of Compound AT (4.5 g, 11.8 mmol) in THF (60 mL)was added di-tert-butyl dicarbonate and palladium hydroxide on carbon(1.0 g). The reaction mixture was heated to 45° C. overnight underpressure hydrogen atmosphere. The reaction mixture was filtrated andconcentrated. The residue was purified by column chromatography to giveCompound AU (3.6 g).

Step 4: To a solution of Compound AU (760 mg, 1.89 mmol) in methanol(4.0 mL) at 55° C. was added dropwise sodium hydroxide (98 mg, 2.46mmol) in water (1 mL). The reaction mixture was stirred at 55° C. for 2hours. The reaction mixture was cooled down and neutralized to pH 3.0,and then extracted with ethyl acetate (30 mL) three times. The combinedorganic phase was dried over Na₂SO₄, filtrated and then concentrated togive crude Compound AV (660 mg).

Step 5: To a solution of Compound AV (776 mg, 2.0 mmol) indichloromethane (8.0 mL) was added cyclopropyl amine (120 mg, 2.0 mmol),HATU (950 mg, 2.5 mmol) and diisopropylethylamine (0.5 mL). The reactionmixture was stirred at room temperature overnight. The reaction mixturewas quenched by adding ice-water, and then extracted withdichloromethane (30 mL) three times. The combined organic phase wasdried over Na₂SO₄, and then filtrated and concentrated to give crudeCompound AW (578 mg).

Step 6: To a mixture of phenylsilane (1.5 mL) and [Ir(COD)₂Cl]₂ (7 mg,0.01 mmol) in dichloromethane (1.5 mL) was added Compound AW (128 mg,2.0 mmol). The reaction mixture was stirred at 40° C. overnight. Thereaction mixture was concentrated and then diluted with dichloromethane(20 mL), then quenched by adding 3 drops of hydrochloride in dioxanesolution (3N). The reaction mixture was washed with water. The organicphase was separated and dried over Na₂SO₄, and then filtrated andconcentrated. The residue was purified by column chromatography to givecrude Compound AX (70 mg).

Step 7: To a solution of Compound AX (72 mg, 0.174 mmol) indichloromethane (2.0 mL) was added 4-nitrophenyl chloroformate (70 mg,0.35 mmol) and diisopropylethylamine (5 drops). After the reactionmixture was heated to 40° C. for 2 hours, it was concentrated and theresidue was purified by column chromatography to give Compound AY (81mg).

Step 8: The mixture of Compound AY (578 mg, 1.0 mmol) and TFA/DCM=2/1 (9mL) was stirred at room temperature for 2 hours. The reaction mixturewas concentrated and added toluene for co-evaporation to removetrifluoroacetic acid. The residue was dissolved in dichloromethane (8.0mL), and then diisopropylethylamine (2 mL) was added. The reactionmixture was heated to 40° C. for 3 hours. The reaction mixture wasconcentrated to give Compound AR (239 mg, crude).

Example 462-[1-[(8aR)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclopropyl]aceticacid

Preparation of Example 46

The title compound was prepared in analogy to Example 1 by using4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]butanoicacid (Compound 46-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 46 wasobtained as a light yellow solid (65 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.96 (d, J=3.3 Hz, 1H), 7.76 (d, J=3.0 Hz, 1H), 7.42 (dd, J=6.1,8.7 Hz, 1H), 7.24 (dd, J=2.8, 8.8 Hz, 1H), 7.05 (dt, J=2.5, 8.4 Hz, 1H),6.17 (s, 1H), 4.15-4.02 (m, 1H), 3.96-3.71 (m, 3H), 3.66-3.53 (m, 4H),3.22-3.07 (m, 2H), 2.90 (d, J=11.0 Hz, 1H), 2.80 (d, J=9.0 Hz, 1H),2.68-2.56 (m, 1H), 2.55-2.46 (m, 1H), 2.37 (dt, J=3.1, 11.6 Hz, 1H),2.18 (t, J=10.9 Hz, 1H), 1.03-0.81 (m, 4H), MS: calc'd 603 (MH⁺),measured 603 (MH⁺).

Preparation of4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]butanoicacid (Compound 46-A)

Step 1: tert-Butyl (3S)-3-formyl-4-methyl-piperazine-1-carboxylate(Compound S, 346 mg, 1 mmol) in dichloromethane (3 mL) and Et₃N (0.5 mL)was added 4-aminobutanoic acid (103 mg, 1 mmol). The reaction mixturewas stirred for 1 hour at room temperature, then concentrated underreduced pressure. Then methanol (5 mL) and sodium cyanoborohydride (248mg, 4 mmol) was added and the reaction mixture was stirred for another 3hours at room temperature. The mixture was concentrated under reducedpressure to give crude compound 46-B.

Step 2: Compound 46-B in THF (10 mL) was added potassium tert-butoxide(224 mg, 2 mmol), the reaction mixture was stirred at 80° C. for 4 h.The solution was cooled to room temperature and acidified to pH 5 withaqueous HCl solution. The mixture was then extracted with ethyl acetate3 times. The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated under reduced pressure to give crude compound46-C (301 mg).

Step 3: To a stirred solution of compound 46-C (301 mg, 0.92 mmol) wasdissolved in dichloromethane (4 mL) and treated with trifluoroaceticacid (2 mL) at room temperature. After the reaction mixture was stirredat room temperature for 1 hour, the solvent was removed in vacuo to give4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]butanoicacid (Compound 46-A) which was used directly.

Example 472-[1-[(8aR)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclopropyl]aceticacid

Preparation of Example 47

The title compound was prepared in analogy to Example 1 by using2-[1-[(8aR)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2yl]cyclopropyl]aceticacid (Compound 47-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 47 wasobtained as a light yellow solid (62 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.96 (d, J=3.3 Hz, 1H), 7.76 (d, J=3.0 Hz, 1H), 7.42 (dd, J=6.1,8.7 Hz, 1H), 7.24 (dd, J=2.8, 8.8 Hz, 1H), 7.05 (dt, J=2.5, 8.4 Hz, 1H),6.17 (s, 1H), 4.15-4.02 (m, 1H), 3.96-3.71 (m, 3H), 3.66-3.53 (m, 4H),3.22-3.07 (m, 2H), 2.90 (d, J=11.0 Hz, 1H), 2.80 (d, J=9.0 Hz, 1H),2.68-2.56 (m, 1H), 2.55-2.46 (m, 1H), 2.37 (dt, J=3.1, 11.6 Hz, 1H),2.18 (t, J=10.9 Hz, 1H), 1.03-0.81 (m, 4H). MS: calc'd 603 (MH⁺),measured 603 (MH⁺).

Preparation of2-[1-[(8aR)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2yl]cyclopropyl]aceticacid (Compound 47-A)

Compound 47-A was prepared in analogy to compound Q in Example 19 byusing methyl 2-(1-aminocyclopropyl)acetate hydrochloride salt (for itssynthesis, refer to: Sandstroem A., et al, Bioorganic & MedicinalChemistry, 16(10), 5590-5605; 2008) instead of ethyl3-amino-2,2-dimethyl-propanoate hydrochloride salt.

Example 482-[1-[(8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclopropyl]aceticacid

Preparation of Example 48

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and2-[1-[(8aR)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2yl]cyclopropyl]aceticacid (Compound 47-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 48 wasobtained as a light yellow solid (76 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.95 (s, 1H), 7.76 (s, 1H), 7.37-7.23 (m, 2H), 7.21-7.10 (m, 1H),6.24 (s, 1H), 4.04 (d, J=7.0 Hz, 3H), 3.95-3.77 (m, 3H), 3.66-3.54 (m,1H), 3.20-3.08 (m, 2H), 2.95-2.86 (m, 1H), 2.86-2.74 (m, 1H), 2.67-2.57(m, 1H), 2.55-2.45 (m, 1H), 2.42-2.30 (m, 1H), 2.23-2.12 (m, 1H), 1.13(t, J=7.2 Hz, 3H), 1.01-0.81 (m, 4H). MS: calc'd 617 (MH⁺), measured 617(MH⁺).

Preparation of ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound C-1)

Compound C-1 was prepared in analogy to compound C by using ethylacetoacetate and 2-chloro-3-fluorobenzaldehyde instead of methylacetoacetate and 2-chloro-4-fluorobenzaldehyde.

Example 49(1S,2R)-2-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid

Preparation of Example 49

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and(1R,2R)-2-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid (Compound 49-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 49 wasobtained as a light yellow solid (48 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.96 (d, J=3.0 Hz, 1H), 7.76 (d, J=3.3 Hz, 1H), 7.27 (s, 2H),7.21-7.12 (m, 1H), 6.24 (s, 1H), 4.47-4.38 (m, 1H), 4.17-3.98 (m, 3H),3.97-3.86 (m, 2H), 3.83-3.75 (m, 1H), 3.59 (s, 1H), 3.25-3.11 (m, 2H),3.03-2.94 (m, 1H), 2.93-2.82 (m, 1H), 2.77-2.68 (m, 1H), 2.45-2.35 (m,1H), 2.29-2.17 (m, 1H), 2.11-1.84 (m, 3H), 1.82-1.68 (m, 3H), 1.13 (t,J=7.2 Hz, 3H). MS: calc'd 631 (MH⁺), measured 631 (MH⁺).

Preparation of(1R,2R)-2-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid (Compound 49-A)

Compound 49-A was prepared in analogy to compound Q in Example 19 byusing ethyl (1R,2R)-2-aminocyclopentanecarboxylate (Accela Chembio Co.,Ltd, SY024586) instead of ethyl 3-amino-2,2-dimethyl-propanoatehydrochloride salt.

Example 50(1R,2R)-2-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid

Preparation of Example 50

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and(1S,2R)-2-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid (Compound 50-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 50 wasobtained as a light yellow solid (30 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.97 (d, J=3.0 Hz, 1H), 7.76 (d, J=3.0 Hz, 1H), 6.97-7.39 (m, 2H),6.24 (s, 1H), 4.42 (d, J=9.8 Hz, 2H), 3.73-4.19 (m, 5H), 3.52 (m, 4H),3.12-3.23 (m, 2H), 2.66-2.96 (m, 2H), 2.11-2.47 (m, 3H), 1.60-2.05 (m,4H), 1.13 ppm (t, J=7.2 Hz, 3H). MS: calc'd 631 (MH⁺), measured 631(MH⁺).

Preparation of(1S,2R)-2-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid (Compound 50-A)

Compound 50-A was prepared in analogy to compound Q in Example 19 byusing ethyl (1S,2R)-2-aminocyclopentanecarboxylate trifluoroacetic acidsalt (compound 50-B) instead of ethyl 3-amino-2,2-dimethyl-propanoatehydrochloride salt.

Preparation of ethyl (1S,2R)-2-aminocyclopentanecarboxylatetrifluoroacetic acid salt (Compound 50-B)

(1R,2S)-2-(Boc-amino)cyclopentanecarboxylate (CAS: 1140972-29-7, TCI) (1mmol) was dissolved in CH₂Cl₂ (3 mL) followed by the slow addition ofTFA (1 mL) at 0° C. The reaction mixture was stirred at rt for 1 hourand then the solvent was removed under vacuum to give the crude product50-B, which was used directly in the next step.

Example 51(1R,2S)-2-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-H-imidazazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxyli

Preparation of Example 51

The title compound was prepared in analogy to Example 1 by using(1R,2S)-2-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid TFA salt (Compound 51-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 51 wasobtained as a light yellow solid (68 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 8.07-7.89 (m, 1H), 7.78 (d, J=3.0 Hz, 1H), 7.44 (t, J=6.9 Hz, 1H),7.25 (dd, J=2.5, 8.8 Hz, 1H), 7.06 (dt, J=2.5, 8.4 Hz, 1H), 6.18 (s,1H), 4.41 (q, J=8.6 Hz, 1H), 4.19 (d, J=16.8 Hz, 1H), 4.05-3.79 (m, 3H),3.64-3.57 (m, 4H), 3.27-3.14 (m, 1H), 3.10 (dd, J=4.3, 9.0 Hz, 1H), 2.99(br. s., 1H), 2.94-2.77 (m, 2H), 2.48 (br. s., 1H), 2.29 (br. s., 1H),2.08-1.84 (m, 3H), 1.84-1.69 (m, 3H). MS: calc'd 617 (MH⁺), measured 617(MH⁺).

Preparation of(1R,2S)-2-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid TFA salt (Compound 51-A)

Compound 51-A was prepared in analogy to compound Q in Example 19 byusing ethyl (1R,2S)-2-aminocyclopentanecarboxylate (Accela Chembio Co.,Ltd, CAS: 197916-36-2) instead of ethyl 3-amino-2,2-dimethyl-propanoatehydrochloride salt.

Example 52(1S,2S)-2-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-H-imidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid

Preparation of Example 52

The title compound was prepared in analogy to Example 1 by using(1S,2S)-2-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid TFA salt (Compound 52-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 52 wasobtained as a light yellow solid (1.7 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 1H NMR (MeOD, 400MHz): d=7.97 (d, J=3.0 Hz, 1H), 7.77 (d, J=3.0Hz, 1H), 7.42 (dd, J=6.0, 8.8 Hz, 1H), 7.24 (dd, J=2.8, 8.8 Hz, 1H),7.06 (dt, J=2.8, 8.4 Hz, 1H), 6.18 (s, 1H), 4.50-4.25 (m, 1H), 4.09 (d,J=17.1 Hz, 1H), 3.98-3.72 (m, 3H), 3.61 (s, 3H), 3.52 (t, J=8.9 Hz, 1H),3.26-3.01 (m, 2H), 2.96-2.72 (m, 3H), 2.41-2.17 (m, 2H), 2.05-1.84 (m,3H), 1.81-1.67 (m, 3H). MS: calc'd 617 (MH⁺), measured 617 (MH⁺).

Preparation of(1S,2S)-2-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid TFA salt (Compound 52-A)

Compound 52-A was prepared in analogy to compound Q in Example 19 byusing ethyl (1S,2S)-2-aminocyclopentanecarboxylate (Accela Chembio Co.,Ltd, CAS: 752181-59-2) instead of ethyl 3-amino-2,2-dimethyl-propanoatehydrochloride salt.

Example 534-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]butanoicacid

Preparation of Example 53

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]butanoicacid (Compound 46-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 53 wasobtained as a light yellow solid (2 mg). ¹H NMR (400 MHz, METHANOL-d₄) dppm 7.97 (d, J=3.0 Hz, 1H), 7.76 (d, J=3.3 Hz, 1H), 7.27 (s, 2H), 7.16(s, 1H), 6.24 (s, 1H), 4.18-4.01 (m, 3H), 3.92 (d, J=16.8 Hz, 3H), 3.49(s, 1H), 3.30-3.25 (m, 1H), 3.25-3.15 (m, 2H), 3.12-3.04 (m, 1H),2.97-2.81 (m, 2H), 2.33 (s, 3H), 2.26-2.14 (m, 1H), 1.85 (d, J=7.0 Hz,2H), 1.13 (t, J=7.2 Hz, 3H). MS: calc'd 605 (MH⁺), measured 605 (MH⁺).

Example 544-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-butanoicacid

Preparation of Example 54

The title compound was prepared in analogy to Example 1 by using4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-butanoicacid TFA salt (Compound 54-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 54 wasobtained as a light yellow solid (23 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 8.01 (d, J=3.0 Hz, 1H), 7.90 (d, J=3.0 Hz, 1H), 7.53 (dd, J=5.9,8.7 Hz, 1H), 7.29 (dd, J=2.6, 8.7 Hz, 1H), 7.17-7.06 (m, 1H), 6.20 (s,1H), 4.77-4.64 (m, 1H), 4.57-4.42 (m, 1H), 4.27-4.12 (m, 1H), 4.07 (dd,J=3.3, 14.8 Hz, 1H), 3.75-3.62 (m, 5H), 3.58 (t, J=9.0 Hz, 1H),3.51-3.37 (m, 2H), 3.27-3.02 (m, 4H), 1.95-1.82 (m, 1H), 1.80-1.66 (m,1H), 1.31-1.19 (m, 6H). MS: calc'd 619 (MH⁺), measured 619 (MH⁺).

Preparation of4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-butanoicacid TFA salt (Compound 54-A)

Step 1: A mixture of 2,2-dimethylbutyrolactone (6.84 g, 60 mmol) and KOH(3.36 g) in H₂O (60 mL) was heated at reflux for 2 h. The solution wascooled to room temperature and acidified to pH 5 with aqueous HClsolution. The mixture was then extracted with ethyl acetate 3 times. Thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated under reduced pressure to give4-hydroxy-2,2-dimethyl-butanoic acid compound 54-B (4 g).

Step 2: To the mixture of compound 54-B (2.2 g, 16.6 mmol) in ethylether (16 mL) and methanol (24 mL) at 0° C. was added a hexane solution(2.0 M) of trimethylsilyldiazomethane (12.5 mL, 25 mmol). The reactionmixture was stirred at 0° C. for 1 h. The solvent was evaporated and theresidue was taken up in ethyl acetate, washed successively with dilutedaqueous HCl solution, saturated NaHCO₃ solution and brine. The mixturewas dried over Na₂SO₄ and concentrated to give4-hydroxy-2,2-dimethyl-butyric acid methyl ester compound 54-C (1.5 g).

Step 3: To a solution of the alcohol 54-C (45 mg, 0.34 mmol) in THF (4mL) at 0° C. were added Ph₃P (136 mg, 0.52 mmol), imidazole (71 mg, 1.04mmol), and I₂ (132 mg, 0.52 mmol). After 1 h, the reaction mixture wasquenched with saturated Na₂S₂O₃ solution. The aqueous layer wasextracted twice with hexanes. The organic layer were dried over Na₂SO₄and concentrated under vacuum to give compound 54-D as a crude product.

Step 4: To a stirred solution of compound M (256 mg, 1 mmol) in DMF (2mL) was added NaH (48 mg, 2 mmol) at room temperature. The reactionmixture was stirred 20 min at room temperature, then compound 54-D (256mg, 1 mmol) was added. After the reaction mixture was stirred for 4hours at room temperature, EA was added and the mixture was washed withwater and brine. The mixture was dried over Na₂SO₄, and concentratedunder reduced pressure to give the crude product, which was purified bycolumn to give compound 54-E (150 mg).

Step 5: To a stirred solution of compound 54-E (150 mg, 0.4 mmol) in THF(5 mL) and water (2 mL) was added LiOH (96 mg 2.4 mmol). After thereaction mixture was stirred at 80° C. for 18 h, it was concentratedunder reduced pressure to give the crude product, which was dissolved inDCM (4 mL) and treated with TFA (4 mL). The mixture was stirred for 2hours at room temperature, then it was concentrated under reducedpressure to give the crude product 54-A which was used directly.

Example 554-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-3,3-dimethyl-butanoicacid

Preparation of Example 55

The title compound was prepared in analogy to Example 1 by using4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-3,3-dimethyl-butanoicacid TFA salt (Compound 55-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 55 wasobtained as a light yellow solid (22 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.96 (d, J=3.3 Hz, 1H), 7.76 (d, J=3.3 Hz, 1H), 7.50-7.35 (m, 1H),7.29-7.20 (m, 1H), 7.12-7.01 (m, 1H), 6.18 (s, 1H), 4.20-4.06 (m, 1H),3.94 (s, 3H), 3.61 (s, 4H), 3.19 (d, J=14.6 Hz, 3H), 3.08-2.99 (m, 1H),2.97-2.82 (m, 2H), 2.47-2.34 (m, 1H), 2.27 (s, 3H), 1.07 (s, 6H). MS:calc'd 619 (MH⁺), measured 619 (MH⁺).

Preparation of4-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-3,3-dimethyl-butanoicacid TFA salt (Compound 55-A)

Step 1: 4,4-Dimethyl-2-pyrrolidinone (2.52 g, 22.3 mmol) was added to amixture of concentrated HCl (50 mL) and water (50 mL) and the resultingmixture was refluxed at 120° C. for 20 hours. After it was cooled toroom temperature, the mixture was washed twice with dichloromethane. Theaqueous layer was evaporated to give 4-amino-3,3-dimethyl-butyric acidhydrochloride compound 55-B (3.4 g) as a white solid.

Step 2: Aldehyde S (346 mg, 1 mmol) in dichloromethane (3 mL) and Et₃N(0.5 mL) was added compound 55-B (131 mg, 1 mmol). The reaction mixturewas stirred for 1 hour at room temperature, then concentrated underreduced pressure. Methanol (5 mL) was added followed by the addition ofsodium cyanoborohydride (248 mg, 4 mmol). After the reaction mixture wasstirred at room temperature for 1 h, it was concentrated under reducedpressure to give crude product 55-C.

Step 3: Compound 55-C in THF (10 mL) was added potassium tert-butoxide(224 mg, 2 mmol), then the reaction mixture was stirred at 80° C. for 4h. The solution was cooled to room temperature and acidified to pH 5with aqueous HCl solution. The mixture was then extracted with ethylacetate 3 times. The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated under reduced pressure to give crudeproduct 55-D.

Step 4: To a stirred solution of compound 55-D (301 mg, 0.92 mmol) indichloromethane (4 mL) was added trifluoroacetic acid (2 mL) at roomtemperature. After the reaction mixture was stirred at room temperaturefor 1 hour, the solvent was removed under vacuum to give crude product55-A which was used directly.

Example 56(R)-6-[(S)-2-(2-Carboxy-ethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

Preparation of Example 56

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]propanoicacid TFA salt (Compound 56-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 56 wasobtained as a light yellow solid (60 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.95-8.00 (m, 1H), 7.79 (d, 1H), 7.25-7.36 (m, 2H), 7.12-7.22 (m,1H), 6.25 (s, 1H), 4.24 (d, 1H), 4.06 (m, 3H), 3.86-4.00 (m, 2H),3.50-3.62 (m, 2H), 3.36-3.50 (m, 1H), 3.24 (m, 1H), 3.15 (m, 1H), 3.04(d, 2H), 2.56 (m, 3H), 2.40 (br. s., 1H), 1.13 (m, 3H). MS: calc'd 591(MH⁺), measured 591 (MH⁺).

Preparation of3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]propanoicacid TFA salt (Compound 56-A)

Step 1: To a stirred solution of compound M (150 mg, 0.62 mmol) in THF(3 mL) was added methyl acrylate (534 mg, 6.20 mmol) at roomtemperature, followed by a small amount of NaOH as a catalyst. LC-MSindicated compound M was consumed completely and the product 56-B wasformed already. The resulting mixture was stirred at rt for 6 hours. Thereaction mixture was then concentrated and directly used in the nextstep without further purification. The crude product amount was 180 mg.

Step 2: To a solution of compound 56-B (180 mg, 0.55 mmol) in THF (3 mL)was added a solution of lithium hydroxide monohydrate (116 mg, 2.75mmol) in H₂O (1 mL) at room temperature. The resulting mixture wasstirred at room temperature for 3 hours. LC-MS showed starting material56-B was consumed completely. The mixture was adjusted to pH 4-5 with 1N HCl, then concentrated. The residue was used directly in the next stepand the amount of crude product 56-C was 300 mg.

Step 3: To a solution of 56-C (crude 300 mg, 0.55 mmol) indichloromethane (3 mL) was added trifluoroacetic acid (3 mL) at roomtemperature. The resulting mixture was stirred at room temperature for 2hours. The reaction mixture was concentrated and the residue wasdirectly used in the next step. The amount of crude product 56-A was 350mg.

Example 57(R)-6-[(S)-2-((R)-2-Carboxyl-1-methyl-ethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

Preparation of Example 57

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and(3R)-3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]butanoicacid TFA salt (Compound 57-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 57 wasobtained as a light yellow solid (48 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 8.02 (d, 1H), 7.91 (d, 1H), 7.33-7.41 (m, 2H), 7.21-7.29 (m, 1H),6.27 (s, 1H), 4.72 (d, 1H), 4.54 (d, 1H), 4.27-4.38 (m, 1H), 4.03-4.19(m, 4H), 3.60-3.74 (m, 3H), 3.38-3.48 (m, 1H), 3.04-3.25 (m, 3H),2.56-2.66 (m, 1H), 2.47-2.56 (m, 1H), 1.27 (d, 3H), 1.13 (m, 3H). MS:calc'd 605 (MH⁺), measured 605 (MH⁺).

Preparation of(3R)-3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]butanoicacid TFA salt (Compound 57-A)

Compound 57-A was prepared in analogy to compound Q in Example 19 byusing methyl (3R)-3-aminobutanoate hydrochloride salt (compound 57-B)instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt.

Preparation of methyl (3R)-3-aminobutanoate hydrochloride salt (Compound57-B)

Compound 57-B was prepared in analogy to compound W in Example 20 byusing (R)-3-aminobutanoic acid instead of DL-3-aminoisobutyric acid.

Example 58(R)-6-[(S)-2-((S)-2-Carboxyl-1-methyl-ethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

Preparation of Example 58

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and(3S)-3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]butanoicacid TFA salt (Compound 58-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 58 wasobtained as a light yellow solid (50 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 8.01 (d, 1H), 7.90 (d, 1H), 7.33-7.40 (m, 2H), 7.21-7.28 (m, 1H),6.27 (s, 1H), 4.66 (d, 1H), 4.49 (d, 1H), 4.34-4.42 (m, 1H), 4.20-4.20(m, 1H), 4.04-4.19 (m, 4H), 3.56-3.66 (m, 3H), 3.42-3.50 (m, 1H), 3.22(m, 1H), 3.01-3.13 (m, 2H), 2.50-2.62 (m, 2H), 1.23 (d, 3H), 1.13 (m,3H). MS: calc'd 605 (MH⁺), measured 605 (MH⁺).

Preparation of(3S)-3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]butanoicacid TFA salt (Compound 58-A)

Compound 58-A was prepared in analogy to compound Q in Example 19 byusing methyl (3S)-3-aminobutanoate hydrochloride salt (compound 58-B)instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt.

Preparation of methyl (3R)-3-aminobutanoate hydrochloride salt (Compound58-B)

Compound 58-B was prepared in analogy to compound W in Example 20 byusing (S)-3-aminobutanoic acid instead of DL-3-aminoisobutyric acid.

Example 59(R)-6-[(S)-2-(1-Carboxy-cyclobutylmethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

Preparation of Example 59

The title compound was prepared in analogy to Example 1 by using1-[[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]methyl]cyclobutanecarboxylicacid TFA salt (Compound 59-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 59 wasobtained as a light yellow solid (15 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.96 (d, 1H), 7.76 (d, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 7.06 (m,1H), 6.17 (s, 1H), 4.08 (d, 1H), 3.90 (d, 2H), 3.82-3.86 (m, 1H),3.66-3.72 (m, 1H), 3.61 (s, 3H), 3.54 (d, 1H), 3.47 (m, 1H), 3.14-3.23(m, 1H), 3.05 (m, 1H), 2.90 (d, 1H), 2.80 (d, 1H), 2.39-2.47 (m, 2H),2.31-2.39 (m, 1H), 2.16 (m, 1H), 1.99-2.09 (m, 3H), 1.89-1.98 (m, 1H).MS: calc'd 617 (MH⁺), measured 617 (MH⁺).

Preparation of1-[[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]methyl]cyclobutanecarboxylicacid TFA salt (Compound 59-A)

Compound 59-A was prepared in analogy to compound Q in Example 19 byusing 1-aminomethyl-cyclobutanecarboxylic acid ethyl ester (for itssynthesis, please refer to: Cao, Sheldon X. et al PCT Int. Appl. (2009),WO 2009067547) instead of ethyl 3-amino-2,2-dimethyl-propanoatehydrochloride salt.

Example 606-[(S)-2-(1-Carboxy-cyclobutylmethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-((R)-2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

Preparation of Example 60

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and1-[[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]methyl]cyclobutanecarboxylicacid TFA salt (Compound 59-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 59 wasobtained as a light yellow solid (15 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.96 (d, 1H), 7.76 (d, 1H), 7.23-7.35 (m, 2H), 7.16 (m, 1H), 6.24(s, 1H), 4.02-4.13 (m, 3H), 3.81-3.97 (m, 3H), 3.65-3.74 (m, 1H),3.43-3.57 (m, 2H), 3.20 (m, 1H), 3.05 (m, 1H), 2.92 (d, 1H), 2.83 (d,1H), 2.31-2.48 (m, 3H), 2.17 (br. s., 1H), 1.92-2.12 (m, 4H), 1.09-1.17(m, 3H). MS: calc'd 631 (MH⁺), measured 631 (MH⁺).

Example 61 (Mixture of 2 Isomers)(R)-6-[(S)-2-((1R,3S)-3-Carboxy-cyclopentyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester and(R)-6-[(S)-2-((1S,3R)-3-Carboxy-cyclopentyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

Preparation of Example 61

The title compound was prepared in analogy to Example 1 by usingcis-3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid TFA salt (Compound 61-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 61 wasobtained as a light yellow solid (30 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.97 (m, 1H), 7.76 (d, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 7.06 (m,1H), 6.17 (s, 1H), 4.24-4.35 (m, 1H), 4.10 (d, 1H), 3.82-3.94 (m, 3H),3.61 (s, 3H), 3.53 (m, 1H), 3.03-3.23 (m, 2H), 2.77-2.93 (m, 3H), 2.36(m, 1H), 2.04-2.23 (m, 2H), 1.67-2.00 (m, 5H). MS: calc'd 617 (MH⁺),measured 617 (MH⁺).

Preparation ofcis-3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid TFA salt (Compound 61-A)

Compound 61-A was prepared in analogy to compound Q in Example 19 byusing cis-methyl 3-aminocyclopentanecarboxylate methyl esterhydrochloride salt (compound 61-B) instead of ethyl3-amino-2,2-dimethyl-propanoate hydrochloride salt.

Preparation of cis-methyl 3-aminocyclopentanecarboxylate methyl esterhydrochloride salt (Compound 61-B)

Compound 61-B was prepared in analogy to compound W in Example 20 byusing cis-3-aminocyclopentanecarboxylic acid (Accela Chembio Co., Ltd,CAS: 49805-32-5) instead of DL-3-aminoisobutyric acid.

Example 62 (Mixture of 2 Isomers)(R)-6-[(S)-2-((1R,3S)-3-Carboxy-cyclopentyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester and(R)-6-[(S)-2-((1S,3R)-3-Carboxy-cyclopentyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

Preparation of Example 62

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) andcis-3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid TFA salt (Compound 61-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 62 wasobtained as a light yellow solid (50 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.97 (m, 1H), 7.76 (d, 1H), 7.23-7.34 (m, 2H), 7.09-7.19 (m, 1H),6.24 (s, 1H), 4.23-4.34 (m, 1H), 4.01-4.15 (m, 3H), 3.83-3.95 (m, 3H),3.53 (m, 1H), 3.04-3.23 (m, 2H), 2.77-2.95 (m, 3H), 2.36 (m, 1H),2.03-2.22 (m, 2H), 1.90-2.00 (m, 2H), 1.68-1.90 (m, 3H), 1.13 (m, 3H).MS: calc'd 631 (MH⁺), measured 631 (MH⁺).

Example 63 (Mixture of Two Isomers)(R)-6-[(S)-2-((1R,3R)-3-Carboxy-cyclopentyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester and(R)-6-[(S)-2-((1S,3S)-3-Carboxy-cyclopentyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

Preparation of Example 63

The title compound was prepared in analogy to Example 1 by usingtrans-3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid TFA salt (Compound 63-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 63 wasobtained as a light yellow solid (10 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.97 (d, 1H), 7.76 (d, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 7.06 (m,1H), 6.17 (s, 1H), 4.39 (d, 1H), 4.10 (d, 1H), 3.84-3.92 (m, 3H), 3.61(s, 3H), 3.49-3.53 (m, 1H), 3.18 (d, 1H), 3.06 (d, 1H), 2.89 (br. s.,3H), 2.38 (d, 1H), 2.07-2.19 (m, 3H), 1.86-1.97 (m, 3H), 1.70 (br. s.,1H). MS: calc'd 617 (MH⁺), measured 617 (MH⁺).

Preparation oftrans-3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid TFA salt (Compound 63-A)

Compound 63-A was prepared in analogy to compound Q in Example 19 byusing trans-methyl 3-aminocyclopentanecarboxylate methyl esterhydrochloride salt (compound 63-B) instead of ethyl3-amino-2,2-dimethyl-propanoate hydrochloride salt.

Preparation of trans-methyl 3-aminocyclopentanecarboxylate methyl esterhydrochloride salt (Compound 63-B)

Compound 63-B was prepared in analogy to compound W in Example 20 byusing trans-3-aminocyclopentanecarboxylic acid (for its synthesis,please refer to: Allan, Robin D.; Fong, Joyce Australian Journal ofChemistry (1986), 39(6), 855-64.) instead of DL-3-aminoisobutyric acid.

Example 64 (Mixture of Two Isomers)(R)-6-[(S)-2-((1R,3R)-3-Carboxy-cyclopentyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester and(R)-6-[(S)-2-((1S,3S)-3-Carboxy-cyclopentyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

Preparation of Example 64

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) andtrans-3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclopentanecarboxylicacid TFA salt (Compound 63-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 64 wasobtained as a light yellow solid (10 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.97 (m, 1H), 7.76 (d, 1H), 7.24-7.34 (m, 2H), 7.12-7.19 (m, 1H),6.24 (s, 1H), 4.34-4.42 (m, 1H), 4.02-4.14 (m, 3H), 3.83-3.94 (m, 3H),3.51 (m, 1H), 3.14-3.22 (m, 1H), 3.04-3.10 (m, 1H), 2.82-2.94 (m, 3H),2.36 (m, 1H), 2.05-2.20 (m, 3H), 1.81-1.98 (m, 3H), 1.65-1.74 (m, 1H),1.13 (m, 3H). MS: calc'd 631 (MH⁺), measured 631 (MH⁺).

Example 65(R)-6-[2-(4-Carboxy-benzyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester

Preparation of Example 65

The title compound was prepared in analogy to Example 1 by using4-[(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)methyl]benzoicacid TFA salt (Compound 65-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 65 wasobtained as a light yellow solid (90 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 8.00-8.06 (m, 3H), 7.91 (m, 1H), 7.53 (m, 1H), 7.40-7.45 (m, 2H),7.30 (m, 1H), 7.08-7.15 (m, 1H), 6.20 (d, 1H), 4.75 (m, 1H), 4.48-4.62(m, 3H), 4.12-4.25 (m, 2H), 3.68-3.78 (m, 2H), 3.65 (d, 3H), 3.44-3.58(m, 2H), 3.16-3.28 (m, 2H), 3.09-3.15 (m, 1H). MS: calc'd 639 (MH⁺),measured 639 (MH⁺).

Preparation of4-[(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)methyl]benzoicacid TFA salt (Compound 65-A)

Compound 65-A was prepared in analogy to compound Q in Example 19 byusing 4-aminomethyl-benzoic acid methyl ester hydrochloride instead ofethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt.

Example 66(R)-6-[2-(4-Carboxy-benzyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

Preparation of Example 66

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and4-[(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)methyl]benzoicacid TFA salt (Compound 65-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 66 wasobtained as a light yellow solid (82 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.99-8.07 (m, 3H), 7.90 (m, 1H), 7.40-7.46 (m, 2H), 7.32-7.39 (m,2H), 7.21-7.29 (m, 1H), 6.26 (d, 1H), 4.75 (m, 1H), 4.47-4.61 (m, 3H),4.13-4.25 (m, 2H), 4.06-4.13 (m, 2H), 3.68-3.78 (m, 2H), 3.44-3.58 (m,2H), 3.18-3.31 (m, 1H), 3.07-3.17 (m, 2H), 1.13 (m, 3H). MS: calc'd 653(MH⁺), measured 653 (MH⁺).

Example 672-[2-[7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]ethoxy]aceticacid

Preparation of Example 67

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and2-[2-(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)ethoxy]aceticacid (Compound 67-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 67 wasobtained as a light yellow solid (2.5 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 8.00-8.01 (d, J=4.0 Hz, 1 H), 7.90-7.89 (d, J=4.0Hz, 1 H),7.35-7.38 (m, 2 H), 7.24 (m, 1 H), 6.26 (s, 1 H), 4.66 (m, 1 H), 4.51(m, 1 H), 4.05-4.40 (m, 5 H), 3.70-3.83 (m, 3 H), 3.52-3.70 (m, 3H),3.40 (m, 3H), 3.32 (m, 2 H), 1.13 (m, 3H). MS: calc'd 621 (MH⁺),measured 621 (MH⁺).

Preparation of2-[2-(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)ethoxy]aceticacid (Compound 67-A)

Step 1: The mixture of methyl (±)-4-Boc-piperazine-2-carboxylate (CAS:129799-08-2, 2.44 g, 0.01 mol), TEA (1.52 g, 0.015 mol) in DCM (10 mL)was added to a solution of (4-nitrophenyl) carbonochloridate (2.42 g,0.012 mol) in DCM (10 mL). After 1 hour at rt, the organic layer waswashed with water and saturated sodium bicarbonate solution, dried oversodium sulfate. After removal of solvent, the crude product 67-B wasobtained and used in the next step without purification. MS: calc'd 410(MH⁺), measured 410 (MH⁺).

Step 2: The mixture of compound 67-B (1.0 g, 2.44 mmol), 2-aminoethanol(1.0 g, 16.4 mmol), TEA (0.49 g, 4.88 mmol), nitromethane (2 mL) washeated at 130° C. with microwave for 3 hours. After removal of solvent,the residue was treated with water, extracted with ethyl acetate.Removal of solvent gave the crude product 67-C. MS: calc'd 300 (MH⁺),measured 300 (MH⁺).

Step 3: A mixture of compound 67-C (730 mg, 2.44 mmol) and BH₃.THF (1M,4.88 mL). After stirring for 24 hours at rt, the mixture was treatedwith saturated sodium bicarbonate aqueous solution, extracted with ethylacetate. After removal of solvent, the product 67-D was obtained. MS:calc'd 286 (MH+), measured 286 (MH+).

Step 4: A mixture of compound 67-D (0.5 g, 1.75 mmol) in THF (15 mL) wasadded t-BuOK (0.294 g, 2.63 mmol). After stirring for 30 minutes,t-butyl bromoacetate (0.68 g, 3.5 mmol) was added into it. Then themixture was stirred for another 2 hours at rt, quenched with water,extracted with ethyl acetate. After removal of solvent, the crudeproduct 67-E was obtained and used in the next step. MS: calc'd 400(MH⁺), measured 400 (MH⁺).

Step 5: A mixture of compound 67-E (0.70 g, 1.75 mmol) in DCM (5 mL) wastreated with TFA (2 mL). After stirring for 1 hour at rt, the solventand residue TFA was removed under reduced pressure to afford the product67-A. MS: calc'd 244 (MH⁺), measured 244 (MH⁺).

Example 682-[3-[7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]propoxy]aceticacid

Preparation of Example 68

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and2-[3-(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)propoxy]aceticacid (Compound 68-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 68 wasobtained as a light yellow solid (6.5 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.99-7.98 (d, J=4.0Hz, 1 H), 7.81-7.82 (d, J=4.0Hz, 1 H), 7.32 (m,2 H), 7.21 (m, 1 H), 6.25 (s, 1 H), 3.90-4.35 (m, 6 H), 3.56 (m, 3 H),3.10-3.40 (m, 4H), 2.60 (m, 2H), 1.85 (m, 2H), 1.15 (m, 3H). MS: calc'd635 (MH⁺), measured 635 (MH⁺).

Preparation of2-[3-(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)propoxy]aceticacid (Compound 68-A)

Compound 68-A was prepared in analogy to Compound 67-A by using3-aminopropan-1-ol instead of 2-aminoethanol.

Example 69 Methyl(4R)-4-(2-chloro-4-fluoro-phenyl)-6-[[2-(5-hydroxy-4,4-dimethyl-pentyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

Preparation of Example 69

The title compound was prepared in analogy to Example 1 by using2-(5-hydroxy-4,4-dimethyl-pentyl)-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one(Compound 69-A) instead of hexahydro-pyrazino[1,2-c][1,3]oxazin-6-one(Compound D). Example 69 was obtained as a light yellow solid (55 mg).¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.97-7.98 (d, J=4.0Hz, 1 H),7.80-7.81 (d, J=4.0Hz, 1 H), 7.45-7.48 (m, 1 H), 7.27 (m, 1 H), 7.08 (m,1H), 6.18 (s, 1 H), 3.80-4.40 (m, 4 H), 3.65 (s, 3 H), 3.55 (m, 1H),3.10-3.30 (m, 6 H), 2.50 (m, 2H), 1.50 (m, 2H), 1.25 (m, 2H), 0.89 (s,6H). MS: calc'd 619 (MH⁺), measured 619 (MH⁺).

Preparation of2-(5-hydroxy-4,4-dimethyl-pentyl)-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one(Compound 69-A)

tert-Butyl2-(5-hydroxy-4,4-dimethyl-pentyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate(Compound 69-B) (1 mmol) was dissolved in CH₂Cl₂ (3 mL) followed by theslow addition of TFA (1 mL) at 0° C. The reaction mixture was stirred atrt for 1 hour and then the solvent was removed under vacuum to give thecrude product 69-A, which was used directly in the next step.

Preparation of tert-butyl2-(5-hydroxy-4,4-dimethyl-pentyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate(Compound 69-B)

Compound 69-B was prepared in analogy to Compound 67-D by using5-amino-2,2-dimethyl-pentan-1-ol instead of 2-aminoethanol.

Example 70 Ethyl(4R)-4-(2-chloro-3-fluoro-phenyl)-6-[[2-(2-hydroxyethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

Preparation of Example 70

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and2-(2-hydroxyethyl)-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one(Compound 70-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 70 wasobtained as a light yellow solid (45 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 8.01-8.02 (d, J=4.0Hz, 1 H), 7.91-7.92 (d, J=4.0Hz, 1 H), 7.38 (m,2 H), 7.27 (m, 1 H), 6.27 (s, 1 H), 4.55-4.78 (m, 2 H), 4.10-4.25 (m, 4H), 3.72 (m, 5 H), 3.45 (m, 2H), 3.10-3.35 (m, 7 H). MS: calc'd 563(MH⁺), measured 563 (MH⁺).

Preparation of2-(2-hydroxyethyl)-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one(Compound 70-A)

tert-Butyl2-(2-hydroxyethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate(Compound 67-D) (1 mmol) was dissolved in CH₂Cl₂ (3 mL) followed by theslow addition of TFA (1 mL) at 0° C. The reaction mixture was stirred atrt for 1 hour and then the solvent was removed in vacuum to give thecrude product 70-A, which was used directly in the next step.

Example 71 Ethyl(4R)-4-(2-chloro-3-fluoro-phenyl)-6-[[2-(2-hydroxyethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

Preparation of Example 71

The title compound was prepared in analogy to Example 1 by using2,2-dimethyl-5-(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)pentanoicacid (Compound 71-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 71 wasobtained as a light yellow solid (45 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 8.01-8.02 (d, J=4.0Hz, 1 H), 7.91-7.92 (d, J=4.0Hz, 1 H), 7.53 (m,1 H), 7.40 (m, 1 H), 7.10 (m, 1H), 6.20 (s, 1 H), 4.52-4.75 (m, 2 H),4.10-4.25 (m, 2 H), 3.65 (m, 5 H), 3.45 (m, 1H), 3.10-3.35 (m, 4 H),1.55 (m, 4H), 1.20 (s, 6H). MS: calc'd 563 (MH⁺), measured 563 (MH⁺).

Preparation of2,2-dimethyl-5-(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)pentanoicacid (Compound 71-A)

Step 1: A mixture of tert-butyl2-(5-hydroxy-4,4-dimethyl-pentyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate(compound 69-B) (0.4 g, 1.1 mmol) and pyridinium dichromate (1.7 g, 4.4mmol) in DMF (10 mL) was stirred for 12 hours, then treated with water,adjusted pH<7 with acetic acid, extracted with ethyl acetate. Afterremoval of solvent, the crude product 71-B was obtained. MS: calc'd 370(MH⁺), measured 370 (MH⁺).

Step 2: A mixture of compound 71-B (0.41 g, 1.1 mmol), TFA (2 mL) in DCM(2 mL) was stirred for 1.2 hours at rt. After removal of solvent andTFA, the crude product 71-A was obtained and used in the next step. MS:calc'd 270 (MH⁺), measured 270 (MH⁺).

Example 724-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclohexanecarboxylicacid

Preparation of Example 72

The title compound was prepared in analogy to Example 1 by usingcis-4-[(2R)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclohexanecarboxylicacid TFA salt (Compound 72-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 72 wasobtained as a light yellow solid (30 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.97 (d, J=3.3 Hz, 1H), 7.77 (d, J=3.0 Hz, 1H), 7.42 (dd, J=8.8,6.3 Hz, 1H), 7.24 (dd, J=8.8, 2.5 Hz, 1H), 7.06 (td, J=8.5, 2.6 Hz, 1H),6.17 (s, 1H), 4.10 (d, J=16.8 Hz, 1H), 3.79-3.97 (m, 3H), 3.55-3.70 (m,4H), 3.48 (t, J=8.9 Hz, 1H), 3.11-3.26 (m, 1H), 3.03 (dd, J=9.3, 4.0 Hz,1H), 2.71-2.96 (m, 3H), 2.04-2.42 (m, 5H), 1.77 (br. s., 2H), 1.46-1.62ppm (m, 3H). MS: calc'd 631 (MH⁺), measured 631 (MH⁺).

Preparation ofcis-4-[(2R)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclohexanecarboxylicacid TFA salt (Compound 72-A)

Compound 72-A was prepared in analogy to compound Q in Example 19 byusing methyl cis-4-aminocyclohexanecarboxylate hydrochloride (CAS:61367-16-6, TCI) instead of ethyl 3-amino-2,2-dimethyl-propanoatehydrochloride salt.

Example 734-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]cyclohexanecarboxylicacid

Preparation of Example 73

The title compound was prepared in analogy to Example 1 by usingtrans-4-[(2R)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclohexanecarboxylicacid TFA salt (Compound 73-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 73 wasobtained as a light yellow solid (46 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.97 (d, J=3.0 Hz, 1H), 7.77 (d, J=3.0 Hz, 1H), 7.42 (dd, J=8.8,6.3 Hz, 1H), 7.24 (dd, J=8.5, 2.8 Hz, 1H), 7.06 (td, J=8.5, 2.5 Hz, 1H),6.17 (s, 1H), 4.10 (d, J=17.1 Hz, 1H), 3.78-3.97 (m, 3H), 3.61 (s, 3H),3.41-3.52 (m, 1H), 3.19 (d, J=11.0 Hz, 1H), 3.03 (dd, J=9.5, 4.0 Hz,1H), 2.75-2.94 (m, 2H), 2.36 (dd, J=11.7, 7.9 Hz, 2H), 1.93-2.24 (m,5H), 1.77 (br. s., 2H), 1.53 ppm (d, J=10.0 Hz, 3H). MS: calc'd 631(MH⁺), measured 631 (MH⁺).

Preparation oftrans-4-[(2R)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]cyclohexanecarboxylicacid TFA salt (Compound 73-A)

Compound 73-A was prepared in analogy to compound Q in Example 19 byusing methyl-trans-4-amino-cyclohexanecarboxylic acid methyl ester (CAS:61367-07-5, TCI) instead of ethyl 3-amino-2,2-dimethyl-propanoatehydrochloride salt.

Example 743-[(8aS)-7-[[(4R)-4-(2-chlorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid

Preparation of Example 74

The title compound was prepared in analogy to Example 1 by using methyl(4R)-6-(bromomethyl)-4-(2-chlorophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound C-2) and3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid (Compound Q) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 74 wasobtained as a light yellow solid (6 mg). ¹H NMR (400 MHz, METHANOL-d₄) dppm 7.97 (d, J=3.3 Hz, 1H), 7.76 (d, J=3.3 Hz, 1H), 7.41 (td, J=7.4, 1.8Hz, 2H), 7.19-7.33 (m, 2H), 6.21 (s, 1H), 4.08 (d, J=17.1 Hz, 1H),3.79-3.96 (m, 3H), 3.60 (s, 2H), 3.51 (t, J=9.2 Hz, 1H), 3.37-3.42 (m,1H), 3.07-3.28 (m, 3H), 2.74-2.94 (m, 2H), 2.12-2.41 (m, 4H), 1.39 (d,J=6.3 Hz, 2H), 1.18 ppm (d, J=4.0 Hz, 3H). MS: calc'd 587 (MH⁺),measured 587 (MH⁺).

Preparation of methyl(4R)-6-(bromomethyl)-4-(2-chlorophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound C-2)

Compound C-2 was prepared in analogy to compound C by using2-chlorobenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde.

Example 752-[[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]methyl]butanoicacid

Preparation of Example 75

The title compound was prepared in analogy to Example 1 by using2-[[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]methyl]butanoicacid TFA salt (Compound 75-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 75 wasobtained as a light yellow solid (50 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.96-7.97 (m, 1H), 7.92 (d, J=3.3 Hz, 1H), 7.54 (dd, J=8.8, 6.0Hz, 1H), 7.30 (dd, J=8.7, 2.6 Hz, 1H), 7.12 (td, J=8.3, 2.6 Hz, 1H),6.20 (s, 1H), 4.64-4.81 (m, 2H), 4.46-4.60 (m, 1H), 4.01-4.26 (m, 2H),3.60-3.78 (m, 5H), 3.35-3.57 (m, 3H), 3.03-3.29 (m, 3H), 2.62 (dtd,J=14.1, 8.4, 5.5 Hz, 1H), 1.50-1.74 (m, 2H), 0.99 ppm (t, J=7.4 Hz, 3H).MS: calc'd 605 (MH⁺), measured 605 (MH⁺).

Preparation of2-[[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]methyl]butanoicacid TFA salt (Compound 75-A)

Compound 75-A was prepared in analogy to compound Q by using methyl2-(aminomethyl)butanoate (for its synthesis, please refer to: Kaptein,Bernardus; et al PCT Int. Appl. 2005, WO 2005085462) instead of ethyl3-amino-2,2-dimethyl-propanoate hydrochloride salt.

Example 763-[(8aS)-7-[[(4S)-5-ethoxycarbonyl-4-(3-fluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid

Preparation of Example 76

The title compound was prepared in analogy to Example 1 by using ethyl(4S)-6-(bromomethyl)-4-(3-fluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound C-3) and3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid (Compound Q) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 76 wasobtained as a light yellow solid (132 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.95 (d, J=3.3 Hz, 1H), 7.75 (d, J=3.3 Hz, 1H), 7.08-7.23 (m, 2H),6.95 (t, J=8.8 Hz, 1H), 5.99 (s, 1H), 4.02-4.17 (m, 3H), 3.79-4.00 (m,3H), 3.36-3.57 (m, 2H), 3.26-3.33 (m, 1H), 3.17-3.25 (m, 1H), 3.11 (dd,J=9.3, 4.0 Hz, 1H), 2.78-2.99 (m, 2H), 2.53 (d, J=2.0 Hz, 3H), 2.39 (dd,J=11.2, 8.2 Hz, 1H), 2.14-2.26 (m, 1H), 1.21 (d, J=2.8 Hz, 6H), 1.15 ppm(t, J=7.2 Hz, 3H). MS: calc'd 599 (MH⁺), measured 599 (MH⁺).

Preparation of ethyl(4S)-6-(bromomethyl)-4-(3-fluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound C-3)

Compound C-3 was prepared in analogy to compound C by using2-methyl-3-fluorobenzaldehyde instead of 2-chloro-4-fluorobenzaldehydeand ethyl acetoacetate instead of methyl acetoacetate.

Example 773-[(8aS)-7-[[4-(4-chlorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid

Preparation of Example 77

The title compound was prepared in analogy to Example 1 by using methyl6-(bromomethyl)-4-(4-chlorophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound C-4) and3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid (Compound Q) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 77 wasobtained as a light yellow solid (60 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 7.99 (dd, J=3.1, 1.4 Hz, 1H), 7.80 (d, J=3.3 Hz, 1H), 7.26-7.42(m, 4H), 5.64-5.82 (m, 1H), 4.06 (dd, J=16.8, 4.3 Hz, 1H), 3.72-3.90 (m,3H), 3.69 (s, 3H), 3.37-3.61 (m, 2H), 3.00-3.24 (m, 2H), 2.55-2.97 (m,3H), 2.11-2.39 (m, 2H), 1.19 ppm (dd, J=4.4, 2.9 Hz, 6H). MS: calc'd 587(MH⁺), measured 587 (MH⁺).

Preparation of methyl6-(bromomethyl)-4-(4-chlorophenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound C-4)

Compound C-4 was prepared in analogy to compound C by using4-chlorobenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde withoutchiral SFC separation of dihydropyrimidine intermediate in Scheme 1-1.

Example 783-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2-methoxy-propanoicacid

Preparation of Example 78

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and2-methoxy-3-(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)propanoicacid TFA salt (Compound 78-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 78 wasobtained as a light yellow solid (25 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 8.01 (d, J=3.3 Hz, 1H), 7.92 (d, J=3.0 Hz, 1H), 7.33-7.43 (m, 2H),7.19-7.30 (m, 1H), 6.27 (s, 1H), 4.76 (d, J=16.1 Hz, 1H), 4.58 (d,J=16.1 Hz, 1H), 3.96-4.21 (m, 6H), 3.41-3.83 (m, 10H), 3.10-3.31 (m,5H), 1.13 ppm (t, J=7.2 Hz, 3H). MS: calc'd 621 (MH⁺), measured 621(MH⁺).

Preparation of2-methoxy-3-(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)propanoicacid TFA salt (Compound 78-A)

Compound 78-A was prepared in analogy to compound Q in Example 19 byusing methyl 2-(aminomethyl)butanoate (for its synthesis, please referto: Liang, Congxin; Feng, Yangbo U.S. Pat. Appl. Publ. 2007, US20070072934) instead of ethyl 3-amino-2,2-dimethyl-propanoatehydrochloride salt.

Example 792-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]spiro[3.3]heptane-6-carboxylicacid

Preparation of Example 79

The title compound was prepared in analogy to Example 1 by using2-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]spiro[3.3]heptane-6-carboxylicacid TFA salt (Compound 79-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 79 wasobtained as a light yellow solid (7 mg). ¹H NMR (400 MHz, METHANOL-d₄) dppm 8.00-7.92 (m, 1H), 7.77 (d, J=3.3 Hz, 1H), 7.42 (dd, J=6.3, 8.5 Hz,1H), 7.24 (dd, J=2.5, 8.8 Hz, 1H), 7.06 (dt, J=2.5, 8.4 Hz, 1H), 6.18(s, 1H), 4.33-4.20 (m, 1H), 4.10 (dd, J=4.4, 16.9 Hz, 1H), 3.96-3.73 (m,4H), 3.66-3.58 (m, 3H), 3.57-3.46 (m, 1H), 3.21-2.97 (m, 3H), 2.95-2.80(m, 2H), 2.73 (d, J=10.3 Hz, 1H), 2.44-2.05 (m, 8H). MS: calc'd 626(MH⁺), measured 626 (MH⁺).

Preparation of2-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]spiro[3.3]heptane-6-carboxylicacid TFA salt (Compound 79-A)

Compound 79-A was prepared in analogy to compound Q in Example 19 byusing methyl 2-aminospiro[3.3]heptane-6-carboxylate hydrochloride salt(PharmaBlock (Nanjing) R&D Co. Ltd, PBLG1036) instead of ethyl3-amino-2,2-dimethyl-propanoate hydrochloride salt.

Example 805-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]pentanoicacid

Preparation of Example 80

The title compound was prepared in analogy to Example 1 by using5-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]pentanoicacid TFA salt (Compound 80-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 80 wasobtained as a light yellow solid (18 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 8.02 (d, J=3.0 Hz, 1H), 7.92 (d, J=3.0 Hz, 1H), 7.54 (ddd, J=1.5,6.0, 8.8 Hz, 1H), 7.30 (dd, J=2.5, 8.5 Hz, 1H), 7.22-7.09 (m, 1H), 6.20(s, 1H), 4.76 (d, J=16.1 Hz, 1H), 4.66-4.39 (m, 1H), 4.20 (td, J=3.4,11.7 Hz, 1H), 4.10 (td, J=4.1, 14.8 Hz, 1H), 3.83-3.56 (m, 6H),3.54-3.38 (m, 1H), 3.30-3.10 (m, 5H), 2.43-2.28 (m, 2H), 1.62 (dd,J=3.1, 5.9 Hz, 4H). MS: calc'd 605 (MH⁺), measured 605 (MH⁺).

Preparation of5-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]pentanoicacid TFA salt (Compound 80-A)

Compound 80-A was prepared in analogy to compound Q in Example 19 byusing methyl 5-aminopentanoate hydrochloride salt instead of ethyl3-amino-2,2-dimethyl-propanoate hydrochloride salt.

Example 813-[[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]methyl]cyclobutanecarboxylicacid

Preparation of Example 81

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and3-[(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)methyl]cyclobutanecarboxylicacid TFA salt (Compound 81-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 81 wasobtained as a light yellow solid (7 mg). ¹H NMR (400 MHz, METHANOL-d₄) dppm 7.99 (d, J=3.0 Hz, 1H), 7.84 (d, J=2.3 Hz, 1H), 7.43-7.28 (m, 2H),7.27-7.13 (m, 1H), 6.25 (s, 1H), 4.52-4.33 (m, 1H), 4.32-4.18 (m, 1H),4.07 (q, J=7.0 Hz, 3H), 3.68-3.47 (m, 2H), 3.32-2.98 (m, 7H), 2.65 (d,J=7.5 Hz, 3H), 2.44-2.27 (m, 2H), 2.10-1.98 (m, 2H), 1.13 (t, J=7.2 Hz,3H). MS: calc'd 631 (MH⁺), measured 631 (MH⁺).

Preparation of3-[(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)methyl]cyclobutanecarboxylicacid TFA salt (Compound 81-A)

Compound 81-A was prepared in analogy to compound Q in Example 19 byusing methyl 3-(aminomethyl)cyclobutanecarboxylate hydrochloride salt(compound 81-B) instead of ethyl 3-amino-2,2-dimethyl-propanoatehydrochloride salt.

Preparation of methyl 3-(aminomethyl)cyclobutanecarboxylatehydrochloride salt (Compound 81-B)

Compound 81-B was prepared in analogy to compound W in Example 20 byusing 3-(aminomethyl)cyclobutanecarboxylic acid (PharmaBlock (Nanjing)R&D Co. Ltd, CAS: 1310729-95-3) instead of DL-3-aminoisobutyric acid.

Example 82A and 82B (Separated Two Single Isomers)(8R,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid; and(8S,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid

Preparation of Example 82A and 82B

To a stirred solution of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C, 176 mg, 0.5 mmol) in dry dimethylformamide (3.0 mL) wasadded diisopropylethylamine (1.0 mL), potassium iodide (125 mg, 0.75mmol) and compound C-1 (250 mg, 0.55 mmol). The reaction mixture wasflushed with nitrogen and heated to 55° C. for 2 hours. The reactionmixture was quenched by adding ice-water, extracted with ethyl acetate(30 mL) three times. The organic phase was separated, dried over Na₂SO₄,filtrated and concentrated. The residue was purified by HPLC to give amixture of two isomers which were further resolved by SFC to give twosingle isomers: 82A-1 (faster eluting, 77.3 mg, yield: 25%) and 82B-1(slower eluting, 93 mg, yield: 30%) with 30% isopropanol (0.05% DEA)/CO₂on ChiralPak AD-3 column. MS: calc'd 617 (MH⁺), measured 617 (MH⁺).

The solution of compound 82A-1 (77.3 mg, 0.125 mmol) in tetrahydrofuran(0.62 mL) was added lithium hydroxide monohydrate (52.7 mg, 1.25 mmol)in water (0.62 mL). After the reaction mixture was stirred at 35° C. for2 hours, it was neutralized with 1N hydrochloride solution to pH 3.0.The mixture was extracted with ethyl acetate (30 mL) three times. Thecombined organic phase was dried over Na₂SO₄, filtrated and thenconcentrated. The residue was purified by Prep-HPLC to give Example 82A(56.2 mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.97 (d, J=3.0 Hz, 1H),7.78 (d, J=3.0 Hz, 1H), 7.34-7.27 (m, 2H), 7.16 (s, 1H), 6.25 (s, 1H),4.31 (d, J=17.3 Hz, 1H), 4.10-4.00 (m, 2H), 3.91 (d, J=16.8 Hz, 1H),3.86-3.75 (m, 2H), 3.62-3.54 (m, 1H), 3.46 (dd, J=5.4, 9.7 Hz, 1H),3.32-3.28 (m, 1H), 3.21-3.08 (m, 1H), 2.90 (br. s., 1H), 2.55 (br. s.,1H), 2.46 (t, J=4.9 Hz, 1H), 1.13 (t, J=7.2 Hz, 3H), 0.77-0.66 (m, 4H).MS: calc'd 603 (MH⁺), measured 603 (MH⁺).

Example 82B (68.3 mg) was prepared in analogy to Example 82A. ¹H NMR(400 MHz, METHANOL-d₄) d ppm 7.96 (d, J=3.3 Hz, 1H), 7.77 (d, J=3.0 Hz,1H), 7.29 (s, 2H), 7.21-7.13 (m, 1H), 6.22 (s, 1H), 4.24 (d, J=17.1 Hz,1H), 4.08-3.95 (m, 3H), 3.89-3.77 (m, 2H), 3.60-3.52 (m, 1H), 3.43 (dd,J=5.3, 9.5 Hz, 1H), 3.32-3.28 (m, 1H), 3.22-3.12 (m, 1H), 3.06 (br. s.,1H), 2.66 (br. s., 1H), 2.50-2.42 (m, 1H), 1.12 (t, J=7.0 Hz, 3H), 0.73(s, 4H). MS: calc'd 603 (MH⁺), measured 603 (MH⁺).

Preparation of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylatetrifluoroacetic acid salt (Compound 82-C)

Step 1: The mixture of compound AV (6.5 g, 16.7 mmol) and borane-THFcomplex solution 1.0 M in THF (40 mL, 40 mmol) was stirred at 32° C.overnight. The reaction mixture was concentrated. The residue wasdissolved in ethyl acetate (60 mL) and added 2.0 mL of hydrogen chloridesolution (4.0 M in dioxane). The mixture was extracted with ethylacetate (50 mL) three times. The combined organic phase was dried overNa₂SO₄, filtrated and concentrated. The residue was purified by columnto give compound 82-C-1 (4.0 g).

Step 2: To a solution of oxalyl chloride (2.0 mL) in dry dichloromethane(60 mL) under nitrogen at −78° C. was added dropwise of dimethylsulfoxide (3.3 mL, 47 mmol) in dry dichloromethane (2.0 mL). Afteraddition, the reaction mixture was stirred for 1 hour at −78° C. Then tothe reaction mixture was added compound 82-C-1 (4.0 g, 10.7 mmol) in drydichloromethane (6.0 mL) dropwise and stirred for another hour at −78°C. The reaction was quenched by adding triethylamine (12 mL, 86 mmol)dropwise over 30 minutes. The resulting mixture was warmed up to roomtemperature, and the organic phase was washed by ice-water, separatedand dried over Na₂SO₄, then filtrated and concentrated to give crudecompound 82-C-2 (3.72 g, crude), which was used directly.

Step 3: To a solution of compound 82-C-2 (930 mg, 2.5 mmol) indichloromethane (10 mL) was added cyclopropylamine (260 μL, 3.75 mmol),catalytic amount of acetic acid (2 drops) and sodiumtriacetoxyborohydride (1.06 g, 5 mmol). The reaction mixture was stirredat room temperature overnight. The reaction was quenched by addingice-water, extracted with dichloromethane (30 mL) two times and theorganic phase was washed with sodium bicarbonate solution and dried overNa₂SO₄, then filtrated and concentrated to give crude compound 82-C-3(1.03 g, crude).

Step 4: The mixture of compound 82-C-3 (1.03 g, 2.5 mmol) indichloromethane (15 mL) was added diisopropylethylamine (1.0 mL) and4-nitrophenyl chloroformate (1.0 g, 5.0 mmol). The reaction mixture wasstirred at 40° C. for 2 hours. The reaction was quenched by addingice-water and extracted with dichloromethane (30 mL) two times. Theorganic phase was washed with sodium bicarbonate solution and dried overNa₂SO₄, then filtrated and concentrated. The residue was purified bycolumn to give compound 82-C-4 (1.4 g).

Step 5: The mixture of compound 82-C-4 (1.4 g, 2.42 mmol) andTFA/DCM=2/1 (6 mL) was stirred at room temperature for 30 minutes. Thereaction mixture was concentrated and added toluene for co-evaporationto remove trifluoroacetic acid. The residue was dissolved indichloromethane (15 mL), and then diisopropylethylamine (2 mL) wasadded. The reaction mixture was heated to 40° C. overnight. To thereaction mixture was added di-tert-butyl dicarbonate (1.1 g, 5.0 mmol)and stirred for another 5 hours. The reaction mixture was quenched byadding ice-water, extracted with ethyl acetate (30 mL) two times. Theorganic phase was separated, dried over Na₂SO₄, filtrated andconcentrated. The residue was purified by column to give compound 82-C-5(680 mg).

Step 6: The mixture of compound 82-C-5 (170 mg, 0.5 mmol) andTFA/DCM=2/1 (3 mL) was stirred at room temperature for 30 minutes. Thereaction mixture was concentrated and added toluene for co-evaporationto remove trifluoroacetic acid to give crude compound 82-C which wasused directly.

Example 83A and 83B (Separated Two Single Isomers)(8R,8aS)-2-cyclopropyl-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid; and(8S,8aR)-2-cyclopropyl-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid

Preparation of Example 83A and 83B

The title two compounds were prepared in analogy to Example 82A and 82Bby using methyl(4S)-6-(bromomethyl)-4-(3,4-difluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-5) instead of ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1).

Example 83A was obtained as a light yellow solid (99 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.95 (d, J=3.3 Hz, 1H), 7.76 (d, J=3.0 Hz, 1H),7.14-7.07 (m, 1H), 7.06-6.98 (m, 1H), 5.93 (s, 1H), 4.29 (d, J=17.1 Hz,1H), 3.88 (d, J=17.3 Hz, 1H), 3.79 (br. s., 2H), 3.62 (s, 3H), 3.55 (s,1H), 3.46 (d, J=5.5 Hz, 1H), 3.26 (d, J=9.8 Hz, 1H), 3.20-3.09 (m, 1H),2.85 (d, J=10.8 Hz, 1H), 2.56 (d, J=2.3 Hz, 3H), 2.54-2.42 (m, 2H),0.78-0.68 (m, 4H). MS: calc'd 587 (MH⁺), measured 587 (MH⁺).

Example 83B was obtained as a light yellow solid (72.9 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.94 (d, J=3.3 Hz, 1H), 7.75 (d, J=3.3 Hz, 1H),7.09 (d, J=4.8 Hz, 2H), 5.90 (s, 1H), 4.21 (d, J=17.1 Hz, 1H), 3.97 (d,J=17.1 Hz, 1H), 3.88-3.76 (m, 2H), 3.61 (s, 3H), 3.58-3.50 (m, 1H),3.46-3.40 (m, 1H), 3.28 (s, 1H), 3.21-3.12 (m, 1H), 3.08-2.99 (m, 1H),2.63 (d, J=3.3 Hz, 1H), 2.56 (d, J=2.3 Hz, 3H), 2.50-2.42 (m, 1H),0.79-0.66 (m, 4H). MS: calc'd 587 (MH⁺), measured 587 (MH⁺).

Example 83A was synthesized from compound 83A-1 (faster eluting) andExample 83B was synthesized from compound 83B-1 (slower eluting) onChiralCel OJ-H column eluting with 25% methanol (0.05% DEA)/CO₂.

Preparation of methyl(4S)-6-(bromomethyl)-4-(3,4-difluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound C-5)

Compound C-5 was prepared in analogy to compound C by using3,4-difluoro-2-methylbenzaldehyde instead of2-chloro-4-fluorobenzaldehyde.

Example 84A and 84B (Separated Two Single Isomers)(8R,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid; and(8S,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid

Preparation of Example 84A and 84B

The title two compounds were prepared in analogy to Example 82A and 82Bby using methyl2-isopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 84-C) instead of trans-methyl2-cyclopropyl-3N-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C).

Example 84A was obtained as a light yellow solid (20.3 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 8.11 (d, J=3.0 Hz, 1H), 8.01 (d, J=3.0 Hz, 1H),7.39 (d, J=2.0 Hz, 2H), 7.28-7.21 (m, 1H), 6.32 (s, 1H), 4.38 (d, J=17.3Hz, 1H), 4.08 (d, J=6.5 Hz, 4H), 3.93-3.82 (m, 2H), 3.62-3.47 (m, 3H),3.24-3.14 (m, 1H), 3.10-3.04 (m, 1H), 2.69 (d, J=3.5 Hz, 1H), 1.25-1.11(m, 9H). MS: calc'd 605 (MH⁺), measured 605 (MH⁺).

Example 84B was obtained as a light yellow solid (32.5 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 8.10 (s, 1H), 8.02 (s, 1H), 7.38 (d, J=4.3 Hz,2H), 7.29-7.23 (m, 1H), 6.30 (s, 1H), 4.36 (d, J=16.6 Hz, 1H), 4.14-4.03(m, 4H), 3.87 (d, J=3.3 Hz, 2H), 3.56 (d, J==9.8 Hz, 2H), 3.50-3.44 (m,1H), 3.20 (s, 2H), 2.77 (d, J=3.5 Hz, 1H), 1.24-1.10 (m, 9H). MS: calc'd605 (MH⁺), measured 605 (MH⁺).

Example 84A was synthesized from compound 84A-1 (faster eluting) andExample 84B was synthesized from compound 84B-1 (slower eluting) onChiralPak AD-3 column eluting with 30% isopropanol (0.05% DEA)/CO₂.

Preparation of methyl2-isopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(Compound 84-C)

Compound 84-C was prepared in analogy to compound 82-C by usingisopropylamine instead of cyclopropylamine.

Example 85A and 85B (Separated Two Single Isomers)(8R,8aS)-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid; and(8S,8aR)-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid

Preparation of Example 85A and 85B

The title two compounds were prepared in analogy to Example 82A and 82Bby using methyl(4S)-6-(bromomethyl)-4-(3,4-difluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-5) instead of ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and methyl2-isopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 84-C) instead of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C).

Example 85A was obtained as a light yellow solid (3.6 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 8.10 (d, J=3.3 Hz, 1H), 7.99 (d, J=3.0 Hz, 1H),7.26-7.19 (m, 1H), 7.14-7.04 (m, 1H), 6.01 (s, 1H), 4.34 (d, J=17.1 Hz,1H), 4.11 (s, 1H), 3.98 (d, J=17.3 Hz, 1H), 3.85 (d, J=4.8 Hz, 2H), 3.65(s, 3H), 3.61-3.54 (m, 1H), 3.50 (s, 2H), 3.22-3.13 (m, 1H), 3.03-2.96(m, 1H), 2.70-2.60 (m, 1H), 2.56 (d, J=2.3 Hz, 3H), 1.20 (dd, J=6.8,14.3 Hz, 6H). MS: calc'd 589 (MH⁺), measured 589 (MH⁺).

Example 85B was obtained as a light yellow solid (2.3 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 8.07 (d, J=3.0 Hz, 1H), 7.96 (d, J=3.3 Hz, 1H),7.25-7.17 (m, 1H), 7.16-7.07 (m, 1H), 5.99 (s, 1H), 4.30 (d, J=16.8 Hz,1H), 4.16-3.99 (m, 2H), 3.92-3.82 (m, 2H), 3.65 (s, 3H), 3.59-3.53 (m,1H), 3.51-3.43 (m, 2H), 3.24-3.09 (m, 2H), 2.78-2.68 (m, 1H), 2.55 (d,J=2.3 Hz, 3H), 1.19 (dd, J=6.8, 14.1 Hz, 6H). MS: calc'd 589 (MH⁺),measured 589 (MH⁺).

Example 85A was synthesized from compound 85A-1 (faster eluting) andExample 85B was synthesized from compound 85B-1 (slower eluting) onChiralPak AD-3 column eluting with 20% isopropanol (0.05% DEA)/CO₂.

Example 86A and 86B (Separated Two Single Isomers)(8R,8aS)-2-tert-butyl-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid; and(8S,8aR)-2-tert-butyl-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid

Preparation of Example 86A and 86B

The title two compounds were prepared in analogy to Example 82A and 82Bby using(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) instead of ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and methyl2-tert-butyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 86-C) instead of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C).

Example 86A was obtained as a light yellow solid (64.8 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.98 (d, J=3.0 Hz, 1H), 7.80 (d, J=3.3 Hz, 1H),7.52-7.45 (i, 1H), 7.24 (dd, J=2.6, 8.7 Hz, 1H), 7.06 (d, J=2.8 Hz, 1H),6.19 (s, 1H), 4.32 (d, J=17.3 Hz, 1H), 3.97 (br. s., 1H), 3.82-3.72 (m,2H), 3.65-3.58 (m, 4H), 3.57-3.51 (m, 1H), 3.42-3.36 (m, 1H), 3.19-3.09(m, 1H), 2.99-2.89 (m, 1H), 2.65-2.53 (m, 1H), 1.41 (s, 9H). MS: calc'd605 (MH⁺), measured 605 (MH⁺).

Example 86B was obtained as a light yellow solid (71.1 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.97 (d, J=3.0 Hz, 1H), 7.78 (d, J=3.0 Hz, 1H),7.46 (dd, J=6.1, 8.7 Hz, 1H), 7.25 (dd, J=2.6, 8.7 Hz, 1H), 7.13-7.05(i, 1H), 6.15 (s, 1H), 4.25 (d, J=17.3 Hz, 1H), 4.03 (br. s., 1H),3.86-3.72 (m, 2H), 3.65-3.57 (m, 4H), 3.55-3.48 (m, 1H), 3.41-3.36 (m,1H), 3.19-3.05 (m, 2H), 2.75-2.62 (m, 1H), 1.40 (s, 9H). MS: calc'd 605(MH⁺), measured 605 (MH⁺).

Example 86A was synthesized from compound 86A-1 (faster eluting) andExample 86B was synthesized from compound 86B-1 (slower eluting) onChiralPak AD-3 column eluting with 25% isopropanol (0.05% DEA)/CO₂.

Preparation of methyl2-tert-butyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(Compound 86-C)

Compound 86-C was prepared in analogy to compound 82-C by usingtert-butylamine instead of cyclopropylamine.

Example 87A and 87B (Separated Two Single Isomers)(8R,8aS)-2-tert-butyl-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid; and(8S,8aR)-2-tert-butyl-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid

Preparation of Example 87A and 87B

The title two compounds were prepared in analogy to Example 82A and 82Bby using methyl2-tert-butyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 86-C) instead of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C).

Compound 87B-1 (Single isomer. Structure is either one of the twostructures showing above): Methyl(8S,8aR)-2-tert-butyl-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylate;or Methyl(8R,8aS)-2-tert-butyl-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C).

Compound 87B-1 was obtained as a light yellow solid (316 mg). ¹H NMR(400 MHz, METHANOL-d₄) d ppm 7.97 (d, J=3.0 Hz, 1H), 7.76 (d, J=3.0 Hz,1H), 7.34-7.23 (m, 2H), 7.16 (t, J=8.5 Hz, 1H), 6.22 (s, 1H), 5.51 (s,2H), 4.14 (d, J=17.1 Hz, 1H), 4.08-4.00 (m, 2H), 3.89 (s, 1H), 3.81-3.69(m, 5H), 3.58-3.52 (m, 1H), 3.35 (br. s., 1H), 3.27 (d, J=9.5 Hz, 1H),3.16-3.04 (m, 1H), 2.95 (d, J=12.3 Hz, 1H), 2.52 (dt, J=3.4, 12.0 Hz,1H), 1.39 (s, 9H), 1.13 (t, J=7.2 Hz, 3H). MS: calc'd 633 (MH⁺),measured 633 (MH⁺)

Example 87A was obtained as a light yellow solid (52.7 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.98 (d, J=3.0 Hz, 1H), 7.79 (d, J=3.0 Hz, 1H),7.35-7.27 (m, 2H), 7.17 (s, 1H), 6.25 (s, 1H), 4.39-4.28 (m, 1H),4.09-4.01 (m, 2H), 3.99-3.86 (m, 1H), 3.76 (d, J=9.8 Hz, 2H), 3.64-3.58(m, 1H), 3.57-3.51 (m, 1H), 3.40-3.36 (m, 1H), 3.13 (br. s., 1H),3.00-2.84 (m, 1H), 2.63-2.47 (m, 1H), 1.41 (s, 9H), 1.13 (t, J=7.2 Hz,3H). MS: calc'd 619 (MH⁺), measured 619 (MH⁺).

Example 87B was obtained as a light yellow solid (61.3 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.96 (d, J=3.3 Hz, 1H), 7.77 (d, J=3.0 Hz, 1H),7.36-7.26 (m, 2H), 7.21-7.14 (m, 1H), 6.22 (s, 1H), 4.27 (d, J=16.8 Hz,1H), 4.09-3.97 (m, 3H), 3.86-3.71 (m, 2H), 3.65-3.55 (m, 1H), 3.55-3.46(m, 1H), 3.39-3.34 (m, 1H), 3.20-3.02 (m, 2H), 2.66 (br. s., 1H), 1.40(s, 9H), 1.13 (t, J=7.2 Hz, 3H). MS: calc'd 619 (MH⁺), measured 619(MH⁺)

Example 87A was synthesized from compound 87A-1 (faster eluting) andExample 87B was synthesized from compound 87B-1 (slower eluting) onChiralPak AD-3 column eluting with 30% isopropanol (0.05% DEA)/CO₂.

Example 88A and 88B (Separated Two Single Isomers)(8R,8aS)-2-tert-butyl-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid; and(8S,8aR)-2-tert-butyl-7-[[(4S)-4-(3,4-difluoro-2-methyl-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid

Preparation of Example 88A and 88B

The title two compounds were prepared in analogy to Example 82A and 82Bby using methyl(4S)-6-(bromomethyl)-4-(3,4-difluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-5) instead of ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and methyl2-tert-butyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 86-C) instead of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C).

Example 88A was obtained as a light yellow solid (37.2 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.97 (d, J=3.3 Hz, 1H), 7.78 (d, J=3.0 Hz, 1H),7.14-7.09 (m, 1H), 7.08-6.99 (m, 1H), 5.94 (s, 1H), 4.32 (d, J=17.1 Hz,1H), 3.91 (d, J=17.1 Hz, 1H), 3.79-3.71 (m, 2H), 3.66-3.58 (m, 4H),3.56-3.50 (m, 1H), 3.36 (d, J=9.8 Hz, 1H), 3.17-3.06 (m, 1H), 2.89 (d,J=11.3 Hz, 1H), 2.56 (d, J=2.3 Hz, 4H), 1.40 (s, 9H). MS: calc'd 603(MH⁺), measured 603 (MH⁺).

Example 88B was obtained as a light yellow solid (61.2 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.95 (d, J=3.3 Hz, 1H), 7.77 (d, J=3.3 Hz, 1H),7.14-7.02 (m, 2H), 5.91 (s, 1H), 4.25 (d, J=17.1 Hz, 1H), 4.01 (d,J=17.1 Hz, 1H), 3.85-3.72 (m, 2H), 3.66-3.56 (m, 4H), 3.54-3.46 (m, 1H),3.37 (br. s., 1H), 3.20-3.02 (m, 2H), 2.69 (d, J=10.3 Hz, 1H), 2.56 (d,J=2.5 Hz, 3H), 1.40 (s, 9H). MS: calc'd 603 (MH⁺), measured 603 (MH⁺).

Example 88A was synthesized from compound 88A-1 (faster eluting) andExample 88B was synthesized from compound 88B-1 (slower eluting) onChiralPak AD-3 column eluting with 30% isopropanol (0.05% DEA)/CO₂.

Example 89 Methyl7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-2,5,6,8-tetrahydro-1H-imidazo[1,5-a]pyrazine-8a-carboxylate

Preparation of Example 89

The title compound was prepared in analogy to Example 1 by using methyl3-oxo-1,2,5,6,7,8-hexahydroimidazo[1,5-a]pyrazine-8a-carboxylate TFAsalt (Compound X) instead of hexahydro-pyrazino[1,2-c][1,3]oxazin-6-one(Compound D).

Example 90A and 90B (Separated Two Single Isomers)2-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-1,1-dimethyl-3-oxo-6,8-dihydro-5H-oxazolo[3,4-a]pyrazin-8a-yl]aceticacid; and2-[(8aR)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-1,1-dimethyl-3-oxo-6,8-dihydro-5H-oxazolo[3,4-a]pyrazin-8a-yl]aceticacid

Preparation of Example 90A and 90B

The title two compounds were prepared in analogy to Example 82A and 82Bby using(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) instead of ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and methyl2-(1,1-dimethyl-3-oxo-5,6,7,8-tetrahydrooxazolo[3,4-a]pyrazin-8a-yl)acetate(compound 90-C) instead of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C).

Example 90A was obtained as a light yellow solid (13 mg). ¹H NMR (400MHz, MeOD) δ ppm 7.92 (d, J=3.3 Hz, 1H), 7.71 (d, J=3.0 Hz, 1H), 7.43(dd, J=6.0, 8.8 Hz, 1H), 7.23 (dd, J=2.5, 8.8 Hz, 1H), 7.06 (dt, J=2.5,8.4 Hz, 1H), 6.16 (s, 1H), 4.21 (d, J=16.3 Hz, 1H), 3.87-3.71 (m, 3H),3.61 (s, 3H), 3.52 (d, J=11.5 Hz, 1H), 3.37 (br, 1H), 2.94 (d, J=11.3Hz, 1H), 2.63 (d, J=16.1 Hz, 1H), 2.46-2.30 (m, 2H), 1.47 (s, 3H), 1.42(s, 3H). LC/MS: calc'd 592 (MH+), exp 592 (MH+).

Example 90B was obtained as a light yellow solid (25 mg). ¹H NMR (400MHz, MeOD) δ ppm 7.96 (d, J=3.0 Hz, 1H), 7.75 (d, J=3.0 Hz, 1H), 7.54(dd, J=6.3, 8.8 Hz, 1H), 7.21 (dd, J=2.8, 8.8 Hz, 1H), 7.06 (dt, J=2.5,8.4 Hz, 1H), 6.16 (s, 1H), 4.09-3.90 (m, 2H), 3.89-3.71 (m, 2H),3.66-3.55 (m, 4H), 3.36 (br, 1H), 2.82 (d, J=8.3 Hz, 1H), 2.72 (d,J=16.8 Hz, 1H), 2.43 (d, J=11.3 Hz, 1H), 2.31 (dt, J=4.0, 11.9 Hz, 1H),1.57 (s, 3H), 1.47 (s, 3H); LC/MS: calc'd 592 (MH+), exp 592 (MH+).

Example 90A was synthesized from compound 90A-1 (faster eluting) andExample 90B was synthesized from compound 90B-1 (slower eluting) onChiralPak AD-3 column eluting with 30% isopropanol (0.05% DEA)/CO₂.

Preparation of methyl2-(1,1-dimethyl-3-oxo-5,6,7,8-tetrahydrooxazolo[3,4-a]pyrazin-8a-yl)acetate(Compound 90-C)

Step 1: To a solution of DIPA (3.67 g, 36 mmol, 1.2 eq) in THF (18 mL)was added n-BuLi (2M, 18 mL, 1.2 eq) dropwise at −78° C. over 15 min andthe mixture was stirred for another 15 min at −78° C. Then compound AH(10.3 g, 30 mmol, 1.0 eq) in THF (30 mL) was added dropwise to thereaction at −78° C., after the addition was completed, the mixture wasstirred for another 30 min at −78° C. BOMCl (7 g, 45 mmol) in THF (20mL) was added dropwise over 20 min at −78° C., the reaction mixture wasstirred for 16 h and the temperature was warmed to rt during thisperiod. The reaction was quenched with 1M HCl (50 mL), extracted with EA(100 mL) two times, the organic layer was dried and concentrated, theresidue was purified on silica gel (EA/PE: 0%-20%) to give compound90-C-1 as colorless oil (8.2 g).

Step 2: A mixture of compound 90-C-1 (8.2 g, 17.6 mmol) and Pd(OH)₂/C(500 mg, 20%) in MeOH (100 mL) was stirred at rt for 2 h under hydrogen,then the solid was filtered off, the filtrate was concentrated and theresidue was purified on silica gel (EA/PE: 0%-40%) to give compound90-C-2 as a colorless oil (6.1 g).

Step 3: To a solution of 90-C-2 (3.74 g, 0.01 mol, 1.0 eq) and imidazole(0.81 g, 0.012 mol, 1.2 eq) in DMF (20 mL) was added TBSCl (1.65 g, 0.11mol, 1.1 eq) slowly at rt, then the mixture was stirred at rt for 16 h,diluted with EA (50 mL) washed with water (50 mL) and brine (50 mL), theorganic layer was dried over Na₂SO₄ and concentrated to give compound90-C-3 as a colorless oil (4.4 g). MS: calc'd 489 (MH⁺), measured 489(MH⁺).

Step 4: To a solution of 90-C-3 (4.4 g, 9 mmol, 1.0 eq) in THF (50 mL)was added CH₃MgBr (3.2M, 15 mL, 5.0 eq) dropwise at −40° C. over 15 min,then the reaction mixture was stirred for 16 h and the temperature waswarmed to rt during this period. The reaction was quenched with 1M HCl(50 mL), extracted with EA (100 mL), the organic layer was dried andconcentrated, and residue was purified on silica gel (EA/PE: 20%-40%) togive compound 90-C-4 as colorless oil (1.9 g). MS: calc'd 415 (MH⁺),measured 415 (MH⁺).

Step 5: A solution of 90-C-4 (1.86 g, 4.5 mmol, 1.0 eq) and TBAF (1 M, 9mL, 2.0 eq) in THF (20 mL) was stirred at rt for 2 h, diluted with EA(50 mL), washed with water (50 mL) and brine (50 mL), the organic layerwas dried over Na₂SO₄ and concentrated, the residue was purified onsilica gel (EA/PE: 30%-70%) to give compound 90-C-5 as colorless oil(1.2 g). MS: calc'd 301 (MH⁺), measured 301 (MH⁺).

Step 6: A solution of 90-C-5 (0.9 g, 3 mmol, 1.0 eq), PPh₃ (1.57 g, 6mmol, 2.0 eq) and imidazole (0.41 g, 6 mmol, 2.0 eq) in THF (20 mL) wasrefluxed for 1 h, then Iodine (1.3 g, 4.5 mmol, 1.5 eq) was added andrefluxed for 2 h. Then reaction diluted with EA (50 mL), washed withwater (50 mL) and brine (50 mL), the organic layer was dried (Na₂SO₄)and concentrated, the residue was purified on silica gel (EA/PE: 0%-25%)to give compound 90-C₁₋₆ as colorless oil (0.61 g). MS: calc'd 411(MH⁺), measured 411 (MH⁺).

Step 7: A mixture of 90-C₁₋₆ (0.61 g, 1.5 mmol, 1.0 eq) and KCN (0.195g, 3 mmol, 2.0 eq) in DMSO (10 mL) was stirred at 80° C. for 16 h. Thenreaction diluted with EA (50 mL), washed with water (50 mL) and brine(50 mL), the organic layer was dried over Na₂SO₄ and concentrated, theresidue was purified on silica gel (EA/PE: 0%-25%) to give compound90-C-7 as colorless oil (0.41 g). MS: calc'd 310 (MH⁺), measured 310(MH⁺).

Step 8: A mixture of 90-C-7 (0.41 g, 1.3 mmol, 1.0 eq) in HCl/MeOH (3M,10 mL) was stirred at 80° C. for 16 h. Then reaction was concentrated togive compound 90-C as white solid (0.36 g). MS: calc'd 243 (MH⁺),measured 243 (MH⁺).

Example 91A and 91B (Separated Two Single Isomers)(8R,8aS)-2-tert-butyl-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid; and(8S,8aR)-2-tert-butyl-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid

Preparation of Example 91A and 91B

The title two compounds were prepared in analogy to Example 82A and 82Bby using methyl2-methyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 91-C) instead of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C).

Example 91A was obtained as a light yellow solid (26 mg). ¹H NMR(400MHz, MeOD) 7.97 (d, J=3.3 Hz, 1H), 7.77 (d, J=3.0 Hz, 1H), 7.36-7.26(m, 2H), 7.22-7.11 (m, 1H), 6.25 (s, 1H), 4.30 (d, J=17.3 Hz, 1H), 4.04(q, J=7.2 Hz, 2H), 3.95-3.82 (m, 3H), 3.61-3.45 (m, 2H), 3.31-3.11 (m,2H), 2.93-2.81 (m, 4H), 2.49 (br, 1H), 1.13 (t, J=7.0 Hz, 3H). LC/MS:calc'd 577 (MH+), exp 577 (MH+).

Example 91B was obtained as a light yellow solid (38 mg). ¹H NMR(400MHz, MeOD) 7.96 (d, J=3.0 Hz, 1H), 7.76 (d, J=3.0 Hz, 1H), 7.39-7.25(m, 2H), 7.17 (td, J=2.0, 7.5, 9.1 Hz, 1H), 6.21 (s, 1H), 4.24 (d,J=16.8 Hz, 1H), 4.04 (q, J=7.1 Hz, 2H), 3.98-3.78 (m, 3H), 3.60-3.42 (m,2H), 3.31-3.16 (m, 2H), 3.04 (d, J=10.3 Hz, 1H), 2.83 (s, 3H), 2.61 (br,1H), 1.12 (t, J=7.0 Hz, 3H). LC/MS: calc'd 577 (MH+), exp 577 (MH+).

Example 91A was synthesized from compound 91A-1 (faster eluting) andExample 91B was synthesized from compound 91B-1 (slower eluting) onChiralPak AD-3 column eluting with 30% isopropanol (0.05% DEA)/CO₂.

Preparation of methyl2-methyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(Compound 91-C)

Compound 91-C was prepared in analogy to compound 82-C by using methylamine instead of cyclopropylamine.

Example 92A and 92B (Separated Two Single Isomers) Methyl(4R)-6-[[(8R,8aS)-2-tert-butyl-8-carbamoyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;and Methyl(4R)-6-[[(8S,8aR)-2-tert-butyl-8-carbamoyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

Preparation of Example 92A and 92B

The title two compounds were prepared in analogy to Example 82A and 82Bby usingtrans-2-tert-butyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxamide(compound 92-C) instead of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C). The crude product was purified by HPLC to give amixture of two isomers which were further resolved by SFC to give twosingle isomers: 92A (faster eluting) and 92B (slower eluting) with 30%isopropanol (0.05% DEA)/CO₂ on ChiralPak AD-3 column.

Example 92A was obtained as a light yellow solid (30 mg). ¹H NMR(400MHz, MeOD) δ=7.97 (d, J=3.0 Hz, 1H), 7.74 (d, J=3.3 Hz, 1H),7.37-7.21 (m, 2H), 7.20-7.08 (m, 1H), 6.20 (s, 1H), 4.18 (d, J=17.1 Hz,1H), 4.02 (q, J=7.0 Hz, 2H), 3.84-3.72 (m, 3H), 3.55 (t, J=8.8 Hz, 2H),3.14 (dt, J=3.5, 12.7 Hz, 1H), 3.05 (d, J=9.3 Hz, 1H), 3.00-2.89 (m,1H), 2.45 (dt, J=3.5, 11.9 Hz, 1H), 1.40 (s, 9H), 1.12 (t, J=7.2 Hz,3H). MS: calc'd 618 (MH⁺), exp 618 (MH⁺).

Example 92B was obtained as a light yellow solid (30 mg). ¹H NMR(400MHz, MeOD) δ=7.98 (d, J=3.0 Hz, 1H), 7.76 (d, J=3.0 Hz, 1H),7.36-7.23 (m, 2H), 7.20-7.09 (m, 1H), 6.25 (s, 1H), 4.24 (d, J=17.3 Hz,1H), 4.04 (q, J=7.1 Hz, 2H), 3.85-3.68 (m, 3H), 3.57 (t, J=8.8 Hz, 1H),3.37-2.35 (m, 1H), 3.20-2.99 (m, 2H), 2.85-2.69 (m, 1H), 2.32 (dt,J=3.4, 12.0 Hz, 1H), 1.49-1.34 (s, 9H), 1.13 (t, J=7.0 Hz, 3H). MS:calc'd 618 (MH⁺), exp 618 (MH⁺).

Preparation oftrans-2-tert-butyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxamide(Compound 92-C)

Step 1: To a solution of compound 92-C-1 (355 mg, 1 mmol) in THF (5 mL)was added lithium hydroxide monohydrate (124 mg, 3 mmol) in water (1mL). After the reaction mixture was stirred at 35° C. for 2 hours, itwas neutralized with 1N hydrochloride solution to pH 3.0. The mixturewas extracted with ethyl acetate (30 mL) three times. The combinedorganic phase was dried over Na₂SO₄, filtrated and then concentrated togive compound 92-C-2 as a white solid (340 mg). MS: calc'd 356 (MH⁺),exp 356 (MH⁺).

Step 2: A mixture of compound 92-C-2 (340 mg, 1 mmol), HATU (380 mg, 1mmol), NH₄Cl (275 mg, 5 mmol) and DIPEA (775 mg, 6 mmol) in THF (10 mL)was stirred 50° C. for 2 hours. Then the undissolved material wasfiltered off and the filtrate was concentrated. The residue was purifiedon silica gel (EA/PE: 0%-40%) to give compound 92-C-3 as a white solid(200 mg). MS: calc'd 355 (MH⁺), exp 355 (MH⁺).

Step 3: A mixture of compound 92-C-3 (200 mg, 0.6 mmol) in DCM/TFA (5mL, 2:1) was stirred at room temperature for 2 hours, then the mixturewas concentrated under reduced pressure to give compound 92-C as aslight yellow oil (200 mg), which was used directly in the next step.MS: calc'd 255 (MH⁺), exp 255 (MH⁺).

Preparation of trans-7-tert-butyl-8-methyl2-tert-butyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7,8-dicarboxylate(Compound 92-C-1)

Compound 92-C-1 was prepared in analogy to compound 82-C-5 by usingtert-butylamine instead of cyclopropylamine.

Example 933-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-propoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid

Preparation of Example 93

The title compound was prepared in analogy to Example 1 by using3-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-propoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid (compound C₁₋₆) and3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid (Compound Q) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 93 wasobtained as a light yellow solid (6 mg). ¹H NMR (400MHz, MeOD) δ=7.96(d, J=3.0 Hz, 1H), 7.75 (d, J=3.0 Hz, 1H), 7.34-7.21 (m, 2H), 7.15 (dt,J=1.6, 8.5 Hz, 1H), 6.24 (s, 1H), 4.19-4.06 (m, 1H), 4.03-3.81 (m, 5H),3.51 (t, J=8.9 Hz, 1H), 3.45-3.37 (m, 1H), 3.33-3.29 (m, 1H), 3.25-3.15(m, 1H), 3.11 (dd, J=4.0, 9.5 Hz, 1H), 2.97-2.78 (m, 2H), 2.41-2.29 (m,1H), 2.19 (t, J=10.9 Hz, 1H), 1.59-1.47 (m, 2H), 1.21 (d, J=2.8 Hz, 6H),0.76 (t, J=7.4 Hz, 3H). MS: calc'd 633 (MH⁺), measured 633 (MH⁺).

Preparation of propyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(Compound C₁₋₆)

Compound C6 was prepared in analogy to compound C by using n-propylacetoacetate instead of methyl acetoacetate.

Example 944-[(8aS)-7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-butanoicacid

Preparation of Example 94

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-1) and(3R)-3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]butanoicacid TFA salt (Compound 54-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 57 wasobtained as a light yellow solid (48 mg). ¹H NMR (MeOD, 400MHz): δ=7.97(d, J=3.3 Hz, 1H), 7.76 (d, J=3.0 Hz, 1H), 7.02-7.39 (m, 3H), 6.24 (s,1H), 3.99-4.16 (m, 2H), 3.73-3.95 (m, 3H), 3.47 (t, J=9.0 Hz, 2H),3.02-3.25 (m, 3H), 2.68-2.97 (m, 2H), 2.10-2.48 (m, 3H), 1.76 (br. s.,2H), 1.23 (s, 6H), 1.13 ppm (t, J=7.2 Hz, 3H). MS: calc'd 633 (MH⁺),measured 633 (MH⁺).

Example 955-[7-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]pyridine-2-carboxylicacid

Preparation of Example 95

The title compound was prepared in analogy to Example 1 by using5-(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)pyridine-2-carboxylicacid TFA salt (Compound 95-A) instead ofhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 95 wasobtained as a light yellow solid (48 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 9.02 (s, 1H), 8.17 (s, 2H), 8.01 (s, 1H), 7.88 (s, 1H), 7.51-7.54(m, 1 H), 7.30-7.28 (m, 1 H), 7.10-7.13 (m, 1 H), 6.20 (s, 1H),4.41-4.63 (m, 2H), 4.17-4.35 (m, 3H), 3.51-3.75 (m, 7 H), 3.01-3.12 (m,2H). MS: calc'd 626 (MH⁺), measured 626 (MH⁺).

Preparation of5-(3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl)pyridine-2-carboxylicacid (Compound 95-A)

Step 1: A solution of 5-bromopyridine-2-carboxylic acid (5.0 g, 24.75mmol) in MeOH (30 mL) was added thionyl chloride (10 mL) dropwise at 0°C. Then the mixture was stirred for 12 hours at 60° C. After removal ofsolvent and the residual thionyl chloride, the crude product methyl5-bromopyridine-2-carboxylate was obtained and used in the next stepwithout further purification.

Step 2: A mixture of methyl 5-bromopyridine-2-carboxylate (compound95-A-1, 0.72 g, 3.28 mmol), tert-butyl3-oxo-1,2,5,6,8,8a-hexahydroimidazo[1,5-a]pyrazine-7-carboxylate(racemic compound M, 0.40 g, 1.64 mmol), bis(dibenzylideneacetone)palladium (94.4 mg, 0.164 mmol),(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (196.8 mg, 0.33 mmol),cesium carbonate (160.4 mg, 4.92 mmol) in dioxane (3 mL) was stirred for3 hours at 130° C. in microwave. After removal of solvent, the residuewas purified by column to afford product 95-A-2 as white solid. MS:calc'd 377 (MH⁺), measured 377 (MH⁺).

Step 3: A mixture of compound 95-A-2 (0.24 g, 0.64 mmol), lithiumhydroxide (0.13 g, 3.2 mmol) in water (2 mL) and MeOH (5 mL) was stirredfor 12 hours at room temperature. The reaction mixture was thenneutralized with 1 N HCl to pH 6, extracted with ethyl acetate. Theorganic layer was dried over sodium sulfate. After removal of solvent,the residue was treated with TFA (2 mL) in DCM (10 mL). After thereaction mixture was stirred for 30 minutes, the solvent was removed togive the crude product, which was used in the next step directly. MS:calc'd 263 (MH⁺), measured 263 (MH⁺).

Example 96(S)-6-[(S)-2-(2-Carboxy-2,2-difluoro-ethyl)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-7-ylmethyl]-4-(3,4-difluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid ethyl ester

Preparation of Example 96

The title compound was prepared in analogy to Example 1 by using ethyl(4S)-6-(bromomethyl)-4-(3,4-difluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-7) and2,2-difluoro-3-((S)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-2-yl)-propionicacid trifluoroacetate salt (Compound 96-A) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 96 wasobtained as a light yellow solid (15 mg). ¹H NMR (400 MHz, METHANOL-d₄)d ppm 8.01 (d, 1H), 7.90 (d, 1H), 7.26 (m, 1H), 7.07-7.15 (m, 1H),5.94-5.98 (m, 1H), 4.69 (d, 1H), 4.51 (d, 1H), 4.05-4.20 (m, 4H),3.86-3.98 (m, 2H), 3.62-3.80 (m, 4H), 3.41-3.52 (m, 1H), 3.07-3.22 (m,3H), 2.52 (d, 3H), 1.15 (m, 3H). MS: calc'd 625 (MH⁺), measured 625(MH⁺).

Preparation of2,2-difluoro-3-((S)-3-oxo-hexahydro-imidazo[1,5-a]pyrazin-2-yl)-propionicacid trifluoroacetate salt (Compound 96-A)

Step 1: To a stirred solution of 3-amino-2,2-difluoro-propionic acidhydrochloride salt (400 mg, 1.10 mmol) in DCM (5 mL) was added DIPEA(142 mg, 1.10 mmol) at 0° C., sequentially followed by a solution ofcompound S (350 mg, 1 mmol) in DCM (5 mL). The reaction mixture wasstirred at 0° C. for five minutes. Then NaBH(OAc)₃ was added to themixture. The resulting mixture was stirred at rt overnight. The reactionmixture was partitioned between DCM and water. The organic layer wasseparated, dried over Na₂SO₄, concentrated in vacuum and isolated togive compound 96-A-1 (320 mg).

Step 2: A mixture of compound 96-A-1 (320 mg, 0.70 mmol) and Pd/C (30mg) in MeOH (5 mL) was stirred with a hydrogen balloon at roomtemperature overnight. The reaction mixture was filtered and thefiltrate was concentrated. The crude product 96-A-2 was obtained (226mg) and used in the next step without further purification.

Step 3: To a solution of compound 96-A-2 (crude 226 mg, 0.70 mmol) indichloromethane (3 ml) was added DIPEA (0.6 mL, 3.50 mmol) at 0° C.,then triphosgene (103 mg, 0.35 mmol) was added to the reaction mixture.The resulting mixture was warmed to rt and stirred overnight. Thereaction mixture was concentrated and the residue was directly used inthe next step. The amount of crude product 96-A-3 was 340 mg.

Step 4: To a solution of compound 96-A-3 (crude 340 mg, 0.70 mmol) indichloromethane (2 mL) was added trifluoroacetic acid (5 mL) at roomtemperature. After the reaction mixture was stirred for 1.5 hours, thesolvent was removed to give the crude product 96-A (260 mg) which wasused directly in the next step.

Preparation of ethyl(4S)-6-(bromomethyl)-4-(3,4-difluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate(compound C-7)

Compound C-7 was prepared in analogy to compound C by using3,4-difluoro-2-methylbenzaldehyde and ethyl acetoacetate instead of2-chloro-4-fluorobenzaldehyde and methyl acetoacetate.

Example 97A and 97B (Separated Two Single Isomers)(8R,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-(cyclopropylmethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid; and(8S,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-(cyclopropylmethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid

Preparation of Example 97A and 97B

The title two compounds were prepared in analogy to Example 82A and 82Bby using trans-methyl2-(cyclopropylmethyl)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 97-C) instead of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C).

Example 97A was obtained as a light yellow solid (25 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.98 (d, J=3.0 Hz, 1H), 7.78 (d, J=3.0 Hz, 1H),7.35-7.26 (m, 2H), 7.20-7.11 (m, 1H), 6.25 (s, 1H), 4.30 (s, 1H),4.10-3.99 (m, 2H), 3.95-3.86 (m, 2H), 3.81 (d, J=11.5 Hz, 1H), 3.68 (d,J=8.0 Hz, 1H), 3.65-3.58 (m, 1H), 3.37-3.34 (m, 2H), 3.25-3.16 (m, 1H),3.25-3.16 (m, 1H), 3.15-3.07 (m, 2H), 2.91 (d, J=11.5 Hz, 1H), 2.60-2.49(m, 1H), 1.13 (t, J=7.2 Hz, 3H), 1.03-0.93 (m, 1H), 0.61-0.53 (m, 2H),0.28-0.23 (m, 2H). MS: calc'd 617 (MH⁺), measured 617 (MH⁺).

Example 97B was obtained as a light yellow solid (19 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.33-7.23 (m, 3H), 7.15 (t, J=8.3 Hz, 1H), 6.22(s, 1H), 4.12-4.02 (m, 3H), 3.95-3.84 (m, 3H), 3.52 (t, J=8.9 Hz, 1H),3.44-3.38 (m, 1H), 3.29 (s, 1H), 3.24-3.09 (m, 2H), 2.93 (d, J=11.0 Hz,1H), 2.84 (d, J=8.5 Hz, 1H), 2.48 (d, J=0.8 Hz, 3H), 2.37 (dt, J=3.4,11.6 Hz, 1H), 2.18 (t, J=10.9 Hz, 1H), 1.21 (d, J=3.0 Hz, 6H), 1.13 (t,J=7.2 Hz, 3H). MS: calc'd 617 (MH⁺), measured 617 (MH⁺).

Example 97A was synthesized from compound 97A-1 (faster eluting) andExample 97B was synthesized from compound 97B-1 (slower eluting) onChiralPak AD-3 column eluting with 30% isopropanol (0.05% DEA)/CO₂.

Preparation of trans-methyl2-(cyclopropylmethyl)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 97-C)

Compound 97-C was prepared in analogy to compound 82-C by usingcyclopropylmethanamine instead of cyclopropylamine.

Example 983-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-(4-methylthiazol-2-yl)-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid

Preparation of Example 93

The title compound was prepared in analogy to Example 1 by using ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-(4-methylthiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(compound C-8) and3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid (Compound Q) instead of(R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylicacid methyl ester (Compound C) andhexahydro-pyrazino[1,2-c][1,3]oxazin-6-one (Compound D). Example 93 wasobtained as a light yellow solid (60 mg). ¹H NMR (400MHz, MeOD)δ=7.33-7.23 (m, 3H), 7.15 (t, J=8.3 Hz, 1H), 6.22 (s, 1H), 4.12-4.02 (m,3H), 3.95-3.84 (m, 3H), 3.52 (t, J=8.9 Hz, 1H), 3.44-3.38 (m, 1H), 3.29(s, 1H), 3.24-3.09 (m, 2H), 2.93 (d, J=11.0 Hz, 1H), 2.84 (d, J=8.5 Hz,1H), 2.48 (d, J=0.8 Hz, 3H), 2.37 (dt, J=3.4, 11.6 Hz, 1H), 2.18 (t,J=10.9 Hz, 1H), 1.21 (d, J=3.0 Hz, 6H), 1.13 (t, J=7.2 Hz, 3H). MS:calc'd 633 (MH⁺), measured 633 (MH⁺).

Preparation of ethyl(4R)-6-(bromomethyl)-4-(2-chloro-3-fluoro-phenyl)-2-(4-methylthiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate(compound C-8)

Compound C-8 was prepared in analogy to compound C by using4-methylthiazole-2-carbonitrile and ethyl acetoacetate instead ofthiazole-2-carbonitrile and methyl acetoacetate.

Example 992-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1-carboxylicacid (Mixture of Two Isomers)

Preparation of Example 99

The title two compounds were prepared in analogy to Example 82A and 82Bby usingtrans-6-oxo-2,3,4,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine-1-carboxylicacid (Compound 99-A) instead of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C) without chiral separation of two trans isomers. Example99 was obtained as a mixture of two isomers (light yellow solid, 79 mg).¹H NMR (400MHz, MeOD) δ=7.95 (d, J=3.0 Hz, 1H), 7.75 (d, J=3.3 Hz, 1H),7.35-7.26 (m, 2H), 7.17 (t, J=8.2 Hz, 1H), 6.22 (s, 1H), 4.25 (d, J=17.1Hz, 1H), 4.08-4.01 (m, 3H), 3.98 (s, 2H), 3.20-3.09 (m, 3H), 2.61 (t,J=12.7 Hz, 1H), 2.52-2.42 (m, 2H), 2.34-2.23 (m, 1H), 2.08-1.97 (m, 1H),1.12 (t, J=7.2 Hz, 3H). MS: calc'd 562 (MH⁺), measured 562 (MH⁺).

Preparation oftrans-6-oxo-2,3,4,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine-1-carboxylicacid (Compound 99-A)

Step 1: To a stirred solution of compound 82-C-2 (12 g, 32.3 mmol) inDCM (100 mL) was added TEA (6.6 g, 64.5 mmol) and ethyl(triphenylphosphoranylidene)acetate (12.3 g, 35.5 mmol). The mixture wasstirred at 25° C. for 15 h. Water (100 mL) was added, and the mixturewas extracted with DCM (100 mL). The organic layer was separated anddried over Na₂SO₄. The solvent was removed and the residue was purifiedby column to give compound 99-A-1 (10 g). ¹H NMR (400MHz, CDCl₃)δ=4.90-4.76 (m, 1H), 4.71-4.48 (m, 1H), 4.24-4.08 (m, 2H), 4.03-3.90 (m,1H), 3.85-3.71 (m, 5H), 3.21-2.87 (m, 2H), 2.31 (dq, J=8.5, 16.5 Hz,2H), 2.22-2.05 (m, 1H), 1.98-1.80 (m, 1H), 1.57-1.40 (m, 21H), 1.33-1.23(m, 3H).

Step 2: To a stirred solution of compound 99-A-1 (20 g, 45.2 mmol) inMeOH (600 mL) was added Pd/C (10 g). The mixture was stirred at 30° C.(50 Psi) for 15 h. The mixture was filtered and the solvent was removedin vacuum to give crude product, which was purified by column to givecompound 99-A-2 (17 g, crude).

Step 3: To a stirred solution of compound 99-A-2 (17 g, 38.2 mmol) inanhydrous DCM (90 mL) was added TFA (180 mL). After the reaction mixturewas stirred for 3 hours, the solvent was removed in vacuum to give crudeproduct 99-A-3 (19 g, crude).

Step 4: To a stirred solution of compound 99-A-3 (11 g, 25.1 mmol) inanhydrous DCM (250 mL) was added DIPEA (16 g, 125.6 mmol). After themixture was refluxed for 4 hours, the solvent was removed to give thecrude product 99-A (7 g), which was used directly in the next step.

Example 101A and 101B (Separated Two Single Isomers)(8R,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isobutyl-3-oxo-5,6,8,8a-tetrahydro-H-imidazo[1,5-a]pyrazine-8-carboxylicacid; and(8S,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-isobutyl-3-oxo-5,6,8,8a-tetrahydro-H-imidazo[1,5-a]pyrazine-8-carboxylicacid

Preparation of Example 101A and 101B

The title two compounds were prepared in analogy to Examples 82A and 82Bby using trans-methyl2-isobutyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 101-C) instead of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C).

Example 101A was obtained as a light yellow solid (10 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.98 (d, J=3.3 Hz, 1H), 7.78 (d, J=3.3 Hz, 1H),7.34-7.27 (m, 2H), 7.19-7.13 (m, 1H), 6.25 (s, 1H), 4.31 (d, J=17.1 Hz,1H), 4.09-4.01 (m, 2H), 3.94-3.86 (m, 2H), 3.83-3.76 (m, 1H), 3.60-3.48(m, 2H), 3.29 (d, J=9.5 Hz, 1H), 3.25-3.16 (m, 1H), 3.10-2.98 (m, 2H),2.90 (d, J=11.0 Hz, 1H), 2.57-2.45 (m, 1H), 1.99-1.88 (m, 1H), 1.13 (t,J=7.0 Hz, 3H), 0.95 (dd, J=4.9, 6.7 Hz, 6H). MS: calc'd 619 (MH⁺),measured 619 (MH⁺).

Example 101B was obtained as a light yellow solid (14 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.96 (d, J=3.3 Hz, 1H), 7.76 (d, J=3.0 Hz, 1H),7.36-7.27 (m, 2H), 7.19-7.14 (m, 1H), 6.21 (s, 1H), 4.24 (d, J=16.8 Hz,1H), 4.07-3.93 (m, 3H), 3.92-3.82 (m, 2H), 3.59-3.45 (m, 2H), 3.29-3.18(m, 2H), 3.03 (dd, J=7.5, 11.0 Hz, 3H), 2.66-2.56 (m, 1H), 1.98-1.88 (m,1H), 1.12 (t, J=7.0 Hz, 3H), 0.94 (d, J=6.8 Hz, 6H). MS: calc'd 619(MH⁺), measured 619 (MH⁺).

Example 101A was synthesized from compound 101A-1 (faster eluting) andExample 101B was synthesized from compound 101B-1 (slower eluting) onChiralPak AD-3 column eluting with 30% isopropanol (0.05% DEA)/CO₂.

Preparation of trans-methyl2-isobutyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(Compound 101-C)

Compound 101-C was prepared in analogy to compound 82-C by using2-methylpropan-1-amine instead of cyclopropylamine.

Example 102A and 102B (Separated Two Single Isomers)(8R,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-8-carboxylicacid; and(8S,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-8-carboxylicacid

Preparation of Example 102A and 102B

The title two compounds were prepared in analogy to Example 82A and 82Bby using trans-methyl3-oxo-1,5,6,7,8,8a-hexahydrooxazolo[3,4-a]pyrazine-8-carboxylate(compound 102-C) instead of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C).

Example 102A was obtained as a light yellow solid (29 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.97 (d, J=3.3 Hz, 1H), 7.78 (d, J=3.0 Hz, 1H),7.35-7.27 (m, 2H), 7.20-7.13 (m, 1H), 6.26 (s, 1H), 4.63-4.53 (m, 1H),4.44 (dd, J=6.0, 9.3 Hz, 1H), 4.28 (d, J=17.1 Hz, 1H), 4.15-3.97 (m,4H), 3.77 (dd, J=2.3, 13.3 Hz, 1H), 3.47 (d, J=9.8 Hz, 1H), 3.30 (d,J=3.5 Hz, 1H), 2.96 (dd, J=2.1, 12.2 Hz, 1H), 2.68-2.58 (m, 1H), 1.13(t, J=7.2 Hz, 3H). MS: calc'd 564 (MH⁺), measured 564 (MH⁺).

Example 102B was obtained as a light yellow solid (27 mg). ¹H NMR (400MHz, METHANOL-d₄) d ppm 7.95 (d, J=3.3 Hz, 1H), 7.77 (d, J=3.0 Hz, 1H),7.35-7.28 (m, 2H), 7.20-7.14 (m, 1H), 6.23 (s, 1H), 4.61-4.53 (m, 1H),4.40 (dd, J=6.3, 9.3 Hz, 1H), 4.23-4.17 (m, 1H), 4.13-4.02 (m, 4H), 3.80(dd, J=2.5, 13.6 Hz, 1H), 3.46 (d, J=9.8 Hz, 1H), 3.39-3.27 (m, 1H),3.08 (dd, J=2.3, 12.3 Hz, 1H), 2.73 (dt, J=3.6, 12.2 Hz, 1H), 1.13 (t,J=7.2 Hz, 3H). MS: calc'd 564 (MH⁺), measured 564 (MH⁺).

Example 102A was synthesized from compound 102A-1 (faster eluting) andExample 102B was synthesized from compound 102B-1 (slower eluting) onChiralPak AD-3 column eluting with 30% isopropanol (0.05% DEA)/CO₂.

Preparation of trans-methyl3-oxo-1,5,6,7,8,8a-hexahydrooxazolo[3,4-a]pyrazine-8-carboxylate(compound 102-C)

Step I: To a stirred solution of compound 82-C-1 (8.6 g, 23 mmol) andpyridine (3.64 g, 46 mmol) in DCM (80 mL) was added a solution of(4-nitrophenyl) carbonochloridate (6.95 g, 34.5 mmol) in DCM (20 mL) at0° C. Then the mixture was warmed to rt and stirred for about 2˜3 hrs.The solvent was diluted with DCM (100 mL) and the mixture was washedsuccessively with 0.6N HCl (50 mL), aq. NaHCO₃ (50 mL) and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated invacuum. The obtained crude product was purified by column chromatographyon silica to get the title product 102-C-1 (9.5 g). ¹H NMR (400 MHz,CDCl₃) d ppm 8.30 (d, J=8.8 Hz, 2H), 7.43 (t, J=8.5 Hz, 2H), 5.30-5.09(m, 1H), 4.88-4.71 (m, 1H), 4.54-4.23 (m, 2H), 4.08-3.93 (m, 1H),3.91-3.77 (m, 5H), 3.33-2.97 (m, 1H), 3.33-2.97 (m, 1H), 1.51-1.47 (t,18H)

Step II: To a solution of compound 102-C-1 (9.5 g, 17.6 mmol) in DCM (70mL) was added TFA (70 mL) at room temperature. Then the mixture wasstirred for about 3 h. The solvent was removed under reduced pressure togive the crude product 102-C-2 (10 g crude) as TFA salt which was usedin the next step without further purification.

Step III: To a stirred solution of compound 102-C-2 (crude, 10 g, 17.6mmol) in DCM (160 mL) was added DIPEA (28 mL) at room temperature. Thenthe mixture was heated to reflux and stirred for about 4 h. The crudeproduct was purified by column chromatography on silica to give thetitle compound 102-C (2 g). MS: calc'd 201 (MH⁺), measured 201 (MH⁺).

Example 103A and 103B (Separated Two Single Isomers) Ethyl(4R)-6-[[(8R,8aS)-2-tert-butyl-8-(hydroxymethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;and Ethyl(4R)-6-[[(8S,8aR)-2-tert-butyl-8-(hydroxymethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

Preparation of Example 103A and 103B

The title two compounds were prepared in analogy to Example 82A-1 and82B-1 by usingtrans-2-tert-butyl-8-(hydroxymethyl)-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one(compound 103-C) instead of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C).

Example 103A (faster eluting on ChiralPak AD-3 column with 30%isopropanol (0.05% DEA)/CO₂) was obtained as a light yellow solid (43mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.95 (d, J=3.0 Hz, 1H), 7.74(d, J=3.0 Hz, 1H), 7.35-7.26 (m, 2H), 7.19-7.11 (m, 1H), 6.25 (s, 1H),4.43 (d, J=17.6 Hz, 1H), 4.13-4.01 (m, 3H), 3.97-3.84 (m, 1H), 3.75 (dd,J=4.0, 12.5 Hz, 1H), 3.69-3.60 (m, 2H), 3.58-3.51 (m, 1H), 3.28 (dd,J=7.2, 8.7 Hz, 1H), 3.01 (dt, J=3.1, 12.4 Hz, 1H), 2.81-2.71 (m, 1H),2.53-2.41 (m, 2H), 1.39 (s, 9H), 1.13 (t, J=7.2 Hz, 3H). MS: calc'd 605(MH⁺), measured 605 (MH⁺).

Example 103B (slower eluting on ChiralPak AD-3 column eluting with 30%isopropanol (0.05% DEA)/CO₂) was obtained as a light yellow solid (25mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.98-7.92 (m, 1H), 7.77-7.70(m, 1H), 7.33-7.23 (m, 2H), 7.19-7.11 (m, 1H), 6.24 (s, 1H), 4.53 (d,J=17.8 Hz, 1H), 4.08-3.95 (m, 3H), 3.74-3.62 (m, 4H), 3.57-3.47 (m, 1H),3.26 (dd, J=7.4, 8.7 Hz, 1H), 3.07-2.99 (m, 1H), 2.94 (d, J=11.8 Hz,1H), 2.61 (dt, J=3.5, 11.8 Hz, 1H), 2.50-2.40 (m, 1H), 1.39 (s, 9H),1.16-1.10 (m, 3H). MS: calc'd 605 (MH⁺), measured 605 (MH⁺).

Preparation of trans-methyl3-oxo-1,5,6,7,8,8a-hexahydrooxazolo[3,4-a]pyrazine-8-carboxylate(Compound 102-C)

Step I: LiOH.H₂O (1.26 g, 30 mmol) in H₂O (10 mL) was added to asolution of compound 92-C-1 (3.55 g, 10 mmol) in methanol (40 mL) at rt.After the mixture was stirred at rt for 5 h, methanol was removed underreduced pressure and the mixture was adjusted to pH=5 with 2N HClsolution. The mixture was extracted with ethyl acetate (50 mL, 3 times).The combined organic phase was dried and concentrated to afford crudeproduct 103-C-1 (3.14 g) which was used in the next step without furtherpurification. MS: calc'd 342 (MH⁺), measured 342 (MH⁺).

Step II: BH₃.THF (1M in THF, 30 mL) was added to a solution of compound103-C-1 (3 g, 8.8 mmol) in THF (20 mL) at rt. After the reaction mixturewas refluxed for 3 hours, it was cooled to 0° C. Methanol was addedslowly to previous reaction mixture to quench the reaction. The solventwas removed and the residue was purified by column chromatography toafford product 103-C-2 (2.47 g). MS: calc'd 328 (MH⁺), measured 328(MH⁺).

Step III: TFA (2 mL) was added to a stirring solution of compound103-C-2 (2 g, 6.1 mmol) in CH₂Cl₂ (20 mL) at rt. After 3 hours, LC-MSindicated that the start materials were consumed. The solvent wasremoved to give the crude product 103-C which was used in the next stepwithout further purification. MS: calc'd 228 (MH⁺), measured 228 (MH⁺).

Example 104A and 104B (Separated Two Single Isomers) Ethyl(4R)-6-[[(8aR)-2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;and Ethyl(4R)-6-[[(8aS)-2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

Preparation of Example 104A and 104B

The title two compounds were prepared in analogy to Example 82A-1 and82B-1 by using2-isopropyl-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one (compound104-C) instead of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C).

Example 104A (faster eluting on ChiralPak AD-3 column with 30%isopropanol (0.05% DEA)/CO₂) was obtained as a light yellow solid (71mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.96 (d, J=3.3 Hz, 1H), 7.75(d, J=3.0 Hz, 1H), 7.32-7.24 (m, 2H), 7.15 (t, J=8.3 Hz, 1H), 6.24 (s,1H), 4.12-4.01 (m, 4H), 3.94-3.85 (m, 2H), 3.80 (dd, J=2.0, 13.3 Hz,1H), 3.51 (t, J=8.9 Hz, 1H), 3.18-3.04 (m, 2H), 2.99 (dd, J=2.8, 10.8Hz, 1H), 2.79-2.67 (m, 1H), 2.29 (t, J=10.9 Hz, 1H), 2.25-2.17 (m, 1H),1.20-1.10 (m, 9H). MS: calc'd 561 (MH⁺), measured 561 (MH⁺).

Example 103B (slower eluting on ChiralPak AD-3 column eluting with 30%isopropanol (0.05% DEA)/CO₂) was obtained as a light yellow solid (77mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.96 (d, J=3.1 Hz, 1H), 7.75(d, J=3.3 Hz, 1H), 7.33-7.23 (m, 2H), 7.15 (t, J=8.5 Hz, 1H), 6.24 (s,1H), 4.13-4.00 (m, 4H), 3.94-3.83 (m, 3H), 3.45 (t, J=8.9 Hz, 1H),3.22-3.12 (m, 1H), 3.00 (dd, J=4.0, 9.3 Hz, 1H), 2.93-2.80 (m, 2H), 2.34(dt, J=3.4, 11.6 Hz, 1H), 2.15 (t, J=10.9 Hz, 1H), 1.18-1.09 (m, 9H).MS: calc'd 561 (MH⁺), measured 561 (MH⁺).

Preparation of2-isopropyl-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one (Compound104-C)

tert-Butyl2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate(compound 104-C-1) (1 mmol) was dissolved in CH₂Cl₂ (3 mL) followed bythe slow addition of TFA (1 mL) at 0° C. After the reaction mixture wasstirred at rt for 1 hour, the solvent was removed in vacuum to give thecrude product 104-C, which was used directly in the next step.

Preparation of tert-Butyl2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate(Compound 104-C-1)

Compound 104-C-1 was prepared in analogy to Compound 67-D by usingiso-propyl amine instead of 2-aminoethanol.

Example 105A and 105B (Separated Two Single Isomers)(8R,8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-(2,2-difluoroethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid; and(8S,8aR)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-2-(2,2-difluoroethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-8-carboxylicacid

Preparation of Example 105A and 105B

The title two compounds were prepared in analogy to Example 82A-1 and82B-1 by using2-(2,2-difluoroethyl)-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one(compound 105-C) instead of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C).

Example 105A (faster eluting on ChiralPak AD-3 column with 30%isopropanol (0.05% DEA)/CO₂) was obtained as a light yellow solid (22mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.97 (d, J=3.3 Hz, 1H), 7.77(d, J=3.0 Hz, 1H), 7.34-7.26 (m, 2H), 7.19-7.12 (m, 1H), 6.25 (s, 1H),6.17-5.83 (m, 1H), 4.31 (d, J=17.1 Hz, 1H), 4.08-4.00 (m, 2H), 3.96-3.86(m, 2H), 3.80 (dd, J=2.0, 13.6 Hz, 1H), 3.74-3.68 (m, 1H), 3.66-3.56 (m,3H), 3.28-3.16 (m, 1H), 2.95-2.87 (m, 2H), 2.53 (dt, J=3.4, 12.0 Hz,1H), 1.13 (t, J=7.2 Hz, 3H). MS: calc'd 627 (MH⁺), measured 627 (MH⁺).

Example 105B (slower eluting on ChiralPak AD-3 column eluting with 30%isopropanol (0.05% DEA)/CO₂) was obtained as a light yellow solid (22mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.96 (d, J=3.0 Hz, 1H), 7.76(d, J=3.0 Hz, 1H), 7.35-7.27 (m, 2H), 7.17 (t, J=8.1 Hz, 1H), 6.21 (s,1H), 6.16-5.83 (m, 1H), 4.23 (d, J=16.6 Hz, 1H), 4.06-4.00 (m, 2H),3.98-3.81 (m, 3H), 3.72-3.66 (m, 1H), 3.65-3.55 (m, 3H), 3.29-3.17 (m,2H), 3.04 (d, J=10.3 Hz, 1H), 2.66-2.54 (m, 1H), 1.12 (t, J=7.2 Hz, 3H).MS: calc'd 627 (MH⁺), measured 627 (MH⁺).

Preparation of2-(2,2-difluoroethyl)-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one(Compound 105-C)

tert-Butyl2-(2,2-difluoroethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate(compound 105-C-1) (1 mmol) was dissolved in CH₂Cl₂ (3 mL) followed bythe slow addition of TFA (1 mL) at 0° C. After the reaction mixture wasstirred at rt for 1 hour, the solvent was removed in vacuum to give thecrude product 105-C, which was used directly in the next step.

Preparation of tert-butyl2-(2,2-difluoroethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate(Compound 105-C-1)

Compound 105-C-1 was prepared in analogy to Compound 67-D by using2,2-difluoroethanamine instead of 2-aminoethanol.

Example 106A and 106B (Separated Two Single Isomers) Ethyl(4R)-6-[[(8aR)-2-(2-hydroxy-2-methyl-propyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;and Ethyl(4R)-6-[[(8aS)-2-(2-hydroxy-2-methyl-propyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]methyl]-4-(2-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate

Preparation of Example 106A and 106B

The title two compounds were prepared in analogy to Example 82A-1 and82B-1 by using2-(2-hydroxy-2-methyl-propyl)-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one(compound 106-C) instead of trans-methyl2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazine-8-carboxylate(compound 82-C).

Example 106A (faster eluting on ChiralPak AD-3 column with 30%isopropanol (0.05% DEA)/CO₂) was obtained as a light yellow solid (18mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.96 (d, J=3.0 Hz, 1H), 7.76(d, J=3.3 Hz, 1H), 7.33-7.24 (m, 2H), 7.15 (t, J=8.2 Hz, 1H), 6.25 (s,1H), 4.14-4.01 (m, 3H), 3.97-3.88 (m, 2H), 3.80 (dd, J=2.0, 13.3 Hz,1H), 3.75-3.69 (m, 1H), 3.36 (d, J=4.3 Hz, 1H), 3.24-3.15 (m, 2H),3.13-3.07 (m, 1H), 3.01 (dd, J=2.9, 10.9 Hz, 1H), 2.76 (d, J=11.3 Hz,1H), 2.36 (t, J=10.9 Hz, 1H), 2.22 (dt, J=3.1, 11.6 Hz, 1H), 1.22 (s,6H), 1.13 (t, J=7.2 Hz, 3H). MS: calc'd 591 (MH⁺), measured 591 (MH⁺).

Example 106B (slower eluting on ChiralPak AD-3 column eluting with 30%isopropanol (0.05% DEA)/CO₂) was obtained as a light yellow solid (26mg). ¹H NMR (400 MHz, METHANOL-d₄) d ppm 7.97 (d, J=3.3 Hz, 1H), 7.76(d, J=3.3 Hz, 1H), 7.34-7.24 (m, 2H), 7.16 (t, J=8.2 Hz, 1H), 6.24 (s,1H), 4.13-4.01 (m, 3H), 3.96-3.84 (m, 3H), 3.66 (t, J=9.2 Hz, 1H),3.30-3.16 (m, 3H), 3.14-3.03 (m, 1H), 2.95-2.83 (m, 2H), 2.36 (dt,J=3.4, 11.6 Hz, 1H), 2.22 (t, J=10.9 Hz, 1H), 1.21 (s, 6H), 1.13 (t,J=7.0 Hz, 3H). MS: calc'd 591 (MH⁺), measured 591 (MH⁺).

Preparation of2-(2-hydroxy-2-methyl-propyl)-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one(Compound 106-C)

tert-Butyl2-(2-hydroxy-2-methyl-propyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate(compound 106-C-1) (1 mmol) was dissolved in CH₂Cl₂ (3 mL) followed bythe slow addition of TFA (1 mL) at 0° C. After the reaction mixture wasstirred at rt for 1 hour, the solvent was removed in vacuum to give thecrude product 106-C, which was used directly in the next step.

Preparation of tert-butyl2-(2,2-difluoroethyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate(Compound 106-C-1)

Compound 105-C-1 was prepared in analogy to Compound 67-D by using1-amino-2-methyl-propan-2-ol instead of 2-aminoethanol.

Example 107 HBV Inhibition Assays

Cells and Culture Conditions:

HepG2.2.15 and HepDE19 are stably-transfected cell lines containing theHBV genome. Both cell lines are derived from the hepatoblastoma cellline Hep G2 (American Type Culture Collection, ATCC® HB-8065™) by thepublished procedures described in references: M A Selles et al. Proc.Natl. Acad. Sci. USA 1987, 84, 1005-1009 and H Guo et al. Journal ofVirology 2007, 81, 12472-12484, respectively. Both cell lines weremaintained in Dulbecco's modified Eagle's medium (DMEM)-F12 mediumsupplemented with 10% fetal bovine serum, 100 U/mL penicillin, 100 μg/mLstreptomycin, and 0.5 mg/mL of G418.

While HepG2.2.15 cells constitutively support HBV replication andproduction of virus particles, HepDE19 cells are inducible bytetracycline. Addition of 1 μg/mL tetracycline in culture mediumsuppresses HBV replication in HepDE19 cells, whereas switching totetracycline-free medium resumes this process.

Anti-HBV Activity In Vitro:

HepG2.2.15 cells were seeded into 96-well plates (3×10⁴ cells in 100 μLmedia per well) and incubated overnight at 37° C. The test compoundswere serially half-log diluted in DMSO, then diluted 100 times inculture media. 100 μL of diluted compounds were added into the plates toreach 0.5% final concentration of DMSO in every well. Five days aftercompound treatment, culture supernatant was collected for furtheranalysis.

For quantitative PCR detection of extracellular HBV DNA, 100 μL ofculture supernatant was collected and processed in MagNA Pure 96 NucleicAcid Purification System (Roche Applied Science) for viral DNAextraction. The extracted samples were subjected to HBV DNAquantification by qPCR. The effective compound concentration at whichHBV replication is inhibited by 50% (EC₅₀) was determined as shown inTable 1.

The compounds of the present invention were tested for their capacity toinhibit a HBV activity and activation as described herein. The Exampleswere tested in the above assays as described herein and found to haveEC₅₀<0.2 μM in HepG2.2.15 assay. Particular compounds of formula (I) orother compounds of the present invention were found to have EC₅₀<0.02 μMin HepG2.2.15 assay.

TABLE 1 Anti-HBV activity data of particular compounds in HepG2.2.15cells Example No. EC₅₀ (μM) Example No. EC₅₀ (μM)  1 0.104  2 0.054  30.023  4 0.003  5 0.159  6 0.014  7 0.014  8 0.011  9 0.064 10 0.057 110.001 12 0.149 13 0.066 14 0.002 15 0.110 16 0.041 17 0.039 18 0.108 190.003 20 0.052 21 0.016 22 0.003 23 0.003 24 0.001 25 0.002 26 0.002 270.003 28 0.030 29 0.007 30 0.095 31 0.100 32 0.199 33 0.030 34 0.008 350.011 36 0.006 37 0.017 38 0.005 39 0.030 40 0.034 41 0.014 42 0.006 430.006 44 0.016 45 0.026 46 0.026 47 0.051 48 0.022 49 0.008 50 0.015 510.031 52 0.030 53 0.019 54 0.008 55 0.005 56 0.026 57 0.032 58 0.019 590.011 60 0.006 61 0.012 62 0.006 63 0.012 64 0.008 65 0.009 66 0.004 670.438 68 0.143 69 0.013 70 0.005 71 0.014 72 0.009 73 0.009 74 0.036 750.024 76 0.007 77 0.146 78 0.387 79 0.008 80 0.032 81 0.010 82A/82B0.145/0.002   83B 0.009 84A/84B 0.045/0.001 85A/85B 0.259/0.006   86B0.004 87A/87B 0.062/0.001   87B-1 0.004 88A/88B 0.677/0.005 89 0.00790A/90B 0.096/0.300 91A/91B 0.150/0.002 92A/92B  0.078/0.0007 93 0.01294 0.004 95 0.011 96 0.150 97A/97B 0.037/0.0009 98 0.011 99 0.014101A/101B  0.040/0.0008 102A/102B 0.147/0.014 103A/103B 0.140/0.010104A/104B 0.131/0.004 105A/105B 0.188/0.003 106A/106B 0.032/0.003

Cytotoxicity and Selectivity Index:

HepDE19 cells were seeded into 96-well plates (5×10³ cells per well) andtreated with compounds for EC₅₀ determination. Five days aftertreatment, cell viability was measured by addition of 20 μL of CCK-8reagent. Two hours after incubation at 37° C., the absorbance atwavelengths of 450 nm and 630 nm (OD₄₅₀ and OD₆₃₀) was recorded by aplate reader. The concentration results in the death of 50% of the hostcells (CC₅₀) of each compound were determined.

The relative effectiveness of the compound in inhibiting viralreplication compared to inducing cell death was defined as theselectivity index (CC₅₀ value/EC₅₀ value). Based on CC₅₀ and EC₅₀ data,selectivity indexes were determined.

Results of CC₅₀ and the corresponding selectivity index are given inTable 2.

TABLE 2 CC₅₀ and selectivity index of particular compounds SelectivitySelectivity Example CC₅₀ index Example CC₅₀ index No. (μM) (CC₅₀/EC₅₀)No. (μM) (CC₅₀/EC₅₀)  4 79 23872 11 52 30635 14 23 13016 19 >100 >3030321 >100 >6211 22 >100 >34482 24 53 37857 26 28 18620 34 81 1065535 >100 >9259 36 >100 >18181 38 100 21276 41 >100 >7194 42 >100 >1562544 >100 >6369 54 >100 >12500 55 >100 >20000 59 >100 >9091 60 68 1133361 >100 >8333 62 >100 >16667 63 91 7583 64 67 8375 65 >100 >11111 66 6015000 70 63 12600 71 >100 >7143 73 70 7778 76 >100 >14286 79 52 6500 8185 8500   82B >100 >50000   83B >100 >11111   84B >100 >100000  85B >100 >16667   86B >100 >25000   87B >100 >100000   88B >100 >2000089 75 10714   91B >100 >50000   92B 66 94285 93 86 7167 94 48 12000  97B >100 >100000 98 73 6636 99 >100 >7142  101B >100 >100000 102B >100 >7142  104B 27 >6750  105B >100 >33333  106B 65 21666

Example 108 Human Microsomal Metabolic Stability

Human Microsomes (BD Gentest) were preincubated with test compound for10 minutes at 37° C. in 100 mM phosphate buffer, pH 7.4. The reactionswere initiated by adding NADPH or NADPH regenerating system to give afinal incubation volume of 400 μL. For NADPH system, the finalincubations contained 1 μM test compound, 0.5 mg/mL liver microsomalprotein, 1 mM NADPH in 100 mM phosphate buffer, pH 7.4. For the NADPHregenerating system, the final incubations contained 1 μM test compound,0.5 mg/mL liver microsomal protein, 3 mM glucose 6-phosphate, 1 mM NADP,3 mM MgCl₂ and 0.05 mg/mL glucose 6-phosphate dehydrogenase in 100 mMphosphate buffer, pH 7.4. After incubation times of 0, 3, 6, 9, 15 and30 minutes at 37° C., 1 sample was obtained from each time point and 50μL of each sample was removed and transferred to 150 μL of methanolsolution which was maintained at 4° C. and contained 2 μM tolbutamide asinternal standard. Following precipitation and centrifugation, theamount of compound remaining in the samples were determined by LC-MS/MS.Controls of no NADPH or no NADPH regenerating system at zero and 30minutes were also prepared and analyzed.

Results of metabolic stability study in human microsome are given inTable 3.

TABLE 3 Metabolic stability in human microsome Human Human MicrosomalMicrosomal Example Clearance Example Clearance number (mL/min/kg) number(mL/min/kg) 19 0.4 20 0.1 21 2.7 25 0.4 28 4.4 29 0.3 30 1.7 31 0.3 321.6 33 2.5 34 1.8 35 0.3 36 4.4 37 2.5 38 2.0 39 0.4 41 2.0 42 2.0 433.1 44 1.7 45 0   46 0   47 0   48 3.8 49 0   50 3.6 51 2.0 52 0.0 535.1 54 4.6 55 0.0 56 0.0 59 2.3 60 0.0 61 0.4 62 1.7 63 5.3 64 5.6 656.2 66 7.1 67 4.7 68 4.5 72 5.2 73 8.1 74 1.0 75 0.0 76 0.8 78 6.7 793.6 80 8.3 81 0.1 82A/82B 1.7/2.7 83A/83B   0.0/2.9 84A/84B 0.0/3.685A/85B 4.9/0   86B 4.7   87B 5.0   88B 4.5 90A/90B 0.3/0   91B 5.8 996.1  101B 6.1  102B 6.2

Example 109 Lysa Solubility

Samples were prepared in duplicate from 10 mM DMSO stock solutions.After evaporation of DMSO with a centrifugal vacuum evaporator, theresidue was solved in 0.05 M phosphate buffer (pH 6.5), stirred for onehour and shook for two hours. After one night, the solution was filteredusing a microtiter filter plate. Then the filtrate and its 1/10 dilutionwere analyzed by direct UV measurement or by HPLC-UV. In addition afour-point calibration curve was prepared from the 10 mM stock solutionsand used for the solubility determination of the compounds. The resultswere in μg/mL. In case the percentage of sample measured in solutionafter evaporation divided by the calculated maximum of sample amount wasover 80%, the solubility was reported as higher than this value.

Results of Lysa are given in Table 4.

TABLE 4 Solubility data of particular compounds Example No. Lysa (μg/mL)Example No. Lysa (μg/mL) 19 >727.0 20 >780.0 21 >786.0 28 337 30 61031 >775.0 32 >701.0 33 >748.0 34 326 35 >754.0 36 485 37 422 38 62739 >770.0 41 >804.0 42 >785.0 44 207 45 >690.0 46 >744 47 >767 48 >80749 312 50 339 51 589 53 >723 54 387 55 470 56 >740 59 >685 60 43661 >742 62 374 63 >751 64 >669 65 194 67 >794 68 >794 71 232 72 551 73564 74 >716 75 >774 76 565 78 >793 79 180 80 >616 81 27982A/82B >765/>760 83A/83B >740/780 84A/84B 570/770 85A/85B >660/770  86B >740   88B >745 90A/90B >730/>740   91B >705 95 307 99 >710  102B>665

Example 110 Cytochrome P450 (Cyp450) Induction Screening Assay_mRNAInduction

Materials

Cell Culture

Human cryopreserved hepatocytes (Life Technologies, Carlsbad, USA) werethawed and cultured in collagen I coated 96-well plates with a densityof 52,000 cells/well. After attachment, medium was changed and cellswere pre-cultured overnight in hepatocyte maintenance medium (HMM;Lonza, Switzerland).

Test compounds were dosed to the cells next morning at an indicatedconcentration (up to 10 μM) in HMM culture media containing gentamycinand a constant 0.1% DMSO. Similarly, dilutions of the positive inducercompounds omeprazole (prototypical inducer of human CYP1A2; finalconcentrations: 1 and 10 μM), phenobarbital (prototypical inducer ofhuman CYP2B6; final concentrations: 100 and 1000 μM) and rifampicin(prototypical inducer of human CYP3A4; final concentrations: 1 and 10μM) were prepared from 1000 fold DMSO stock solutions in HMM containinggentamycin. Medium change was then performed and cells were exposed for24 hours to test compounds, positive inducer compounds, or vehicle (0.1%DMSO), respectively.

At the end of the compound exposure period, medium was removed and cellslysed using 100 μL/well MagNA Pure LC RNA isolation tissue lysis buffer(Roche Diagnostics AG, Rotkreuz, Switzerland). Plates were then sealedand frozen at −80° C. until further workup.

mRNA Isolation, Processing and qRT-PCR

mRNA isolation was performed using the MagNA Pure 96 system (RocheDiagnostics AG, Rotkreuz, Switzerland) and the respective cellular RNAlarge volume kit (Roche Diagnostics AG, Rotkreuz, Switzerland) fromthawed samples diluted 1:1 with PBS. The volume of the cell lysis and anelution volume of 100 μL were used. 20 μL of the resulting mRNAsuspension was then used for reverse transcription using 20 μL of thetranscript or first stand cDNA synthesis kit (Roche prime Supply,Mannheim, Germany). The resulting cDNA was diluted with 40 μL of H₂Obefore using for qRT-PCR. qRT-PCR was performed by using the forward andthe reverse primer, the corresponding UPL (all from Microsynth, Balgach,Switzerland) and the Taqman Fast advanced master mix (AppliedBiosystems), on an ABI 7900 machine (Applied Biosystems).

Calculations

qRT-PCR Ct-values for the respective P450s were put into relation to theCt-value of RN18S1 (microsynth, Balgach, Switzerland) of the samesample. Doing so, a respective Δct-value was calculated. Using theaverage of all Δct-values for the vehicle control samples, a ΔΔct-valuewas calculated for each sample(ΔΔct-value(sample)=Δct-value(sample)−average of Δct-value of allvehicle controls). The fold induction of the respective sample wascalculated as 2^(−ΔΔct). The individual fold induction values were thenaveraged per treatment condition (usually n=3 biological replicates).

Relative induction values to the respective positive inducer compoundcondition (10 μM omeprazole for CYP1A2; 1000 μM Phenobarbital forCYP2B6; 10 μM rifampicin for CYP3A4) were then calculated from the foldinduction values as follows:Relative induction (%)=100×(T−V)/(P−V)

T: fold induction of test compound condition

P: fold induction of positive inducer compound

V: fold induction of vehicle controls

Results of CYP3A4 induction are given in Table 5.

TABLE 5 Relative induction values of particular compounds to 10 μMrifampicin Example No. % of Positive control (10 μM Rifampicin) 11 17 191 21 2.4 22 0 25 0 27 0.2 30 7.3 34 0.2 36 6 38 0.2 42 0.6 43 0.2 45 2054 0 55 0.1 59 2.2 62 0 73 0 76 1.3   82B 6   86B 11   87B 4.0   88B 3.7  91B 1.7

The invention claimed is:
 1. A compound of formula (I)

wherein R¹ is hydrogen, halogen or C₁₋₆alkyl; R² is hydrogen or halogen;R³ is hydrogen or halogen; R⁴ is C₁₋₆alkyl; R⁵ is hydrogen or carboxy;R⁶ is hydrogen, C₁₋₆alkoxycarbonyl or carboxy-C_(m)H_(2m)—; X iscarbonyl or sulfonyl; Y is —CH₂—, —O— or —N(R⁷)—, wherein R⁷ ishydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkoxycarbonyl-C_(m)H_(2m)—,—C_(m)H_(2m)—COOH, —(C₁₋₆alkoxy)C₁₋₆alkyl-COOH,—C₁₋₆alkyl-O—C₁₋₆alkyl-COOH, —C₃₋₇cycloalkyl-C_(m)H_(2m)—COOH,—C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH, hydroxy-C_(m)H_(2m)—,carboxyspiro[3.3]heptyl or carboxyphenyl-C_(m)H_(2m)—; W is —CH₂—,—C(C₁₋₆alkyl)₂-, —O— or carbonyl; n is 0 or 1; and m is 0-7; or apharmaceutically acceptable salts or enantiomer thereof.
 2. A compoundaccording to claim 1, wherein R¹ is hydrogen, chloro, bromo or methyl;R² is hydrogen or fluoro; R³ is hydrogen, chloro or fluoro; R⁴ is methylor ethyl; R⁵ is hydrogen or carboxy; R⁶ is hydrogen, methyl-O-carbonylor carboxymethyl; X is carbonyl or sulfonyl; Y is —CH₂—, —O—, —N(R⁷)—,wherein R⁷ is hydrogen, methyl, isopropyl, t-butyl, cyclopropyl,methyl-O-carbonylisopropyl, carboxyethyl, carboxypropyl, carboxybutyl,carboxy(gemdimethyl)methyl, carboxy(gemdimethyl)ethyl,carboxy(gemdimethyl)propyl, carboxy(gemdimethyl)butyl,carboxy(methyl)ethyl, carboxy(ethyl)ethyl, carboxy(methoxy)ethyl,carboxycyclobutyl, carboxycyclobutylmethyl, carboxycyclopentyl,carboxycyclohexyl, carboxymethylcyclopropyl, carboxycyclopropylmethyl,carboxycyclobutylmethyl, carboxyspiro[3.3]heptyl, carboxymethoxyethyl,carboxymethoxypropyl, hydroxyethyl, hydroxymethyl(gemdimethyl)butyl,carboxyphenyl or carboxyphenylmethyl; W is —CH₂—, —C(CH₃)₂—, —O— orcarbonyl; and n is 0 or 1; or a pharmaceutically acceptable salt, orenantiomer thereof.
 3. A compound of formula (IA) according to claim 1,

wherein R¹ is halogen or C₁₋₆alkyl; R² is hydrogen or halogen; R³ ishydrogen or halogen; R⁴ is C₁₋₆alkyl; R⁵ is hydrogen or carboxy; R⁶ ishydrogen, C₁₋₆alkoxycarbonyl or carboxy-C_(m)H_(2m)—; Y is —N(R⁷)—,wherein R⁷ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₁₋₆alkoxycarbonyl-C_(m)H_(2m)—, —C_(m)H_(2m)—COOH,—(C₁₋₆alkoxy)C₁₋₆alkyl-COOH, —C₁₋₆alkyl-O—C₁₋₆alkyl-COOH,—C₃₋₇cycloalkyl-C_(m)H_(2m)—COOH, —C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH,hydroxy-C_(m)H_(2m)—, carboxyspiro[3.3]heptyl orcarboxyphenyl-C_(m)H_(2m)—; W is —CH₂— or carbonyl; and m is 0-7; or apharmaceutically acceptable salt, or enantiomer thereof.
 4. A compoundaccording to claim 1, wherein R¹ is chloro, bromo or methyl; R² ishydrogen or fluoro; R³ is hydrogen, chloro or fluoro; R⁴ is methyl orethyl; R⁵ is hydrogen or carboxy; R⁶ is hydrogen, methyl-O-carbonyl orcarboxymethyl; Y is —N(R⁷)—, wherein R⁷ is hydrogen, methyl, isopropyl,t-butyl, cyclopropyl, methyl-O-carbonylisopropyl, carboxyethyl,carboxypropyl, carboxybutyl, carboxy(gemdimethyl)methyl,carboxy(gemdimethyl)ethyl, carboxy(gemdimethyl)propyl,carboxy(gemdimethyl)butyl, carboxy(methyl)ethyl, carboxy(ethyl)ethyl,carboxy(methoxy)ethyl, carboxycyclobutyl, carboxycyclobutylmethyl,carboxycyclopentyl, carboxycyclohexyl, carboxymethylcyclopropyl,carboxycyclopropylmethyl, carboxycyclobutylmethyl,carboxyspiro[3.3]heptyl, carboxymethoxyethyl, carboxymethoxypropyl,hydroxyethyl, hydroxymethyl(gemdimethyl)butyl, carboxyphenyl orcarboxyphenylmethyl; and W is —CH₂— or carbonyl; or a pharmaceuticallyacceptable salt or enantiomer thereof.
 5. A compound of formula (IAA)according to claim 1,

wherein R¹ is halogen or C₁₋₆alkyl; R² is hydrogen or halogen; R³ ishydrogen or halogen; R⁴ is C₁₋₆alkyl; R⁵ is hydrogen or carboxy; R⁶ ishydrogen; R⁷ is C₁₋₆alkyl, C₃₋₇cycloalkyl, —C_(m)H_(2m)—COOH,—C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH or carboxyphenyl; and m is 1-6; or apharmaceutically acceptable salt, or enantiomer thereof.
 6. A compoundaccording to claim 1, wherein R¹ is chloro or methyl; R² is hydrogen orfluoro; R³ is hydrogen or fluoro; R⁴ is methyl or ethyl; R⁵ is hydrogenor carboxy; R⁶ is hydrogen; and R⁷ is methyl, isopropyl, t-butyl,cyclopropyl, carboxy(gemdimethyl)ethyl, carboxy(gemdimethyl)propyl,carboxycyclopropylmethyl, carboxycyclobutylmethyl or carboxyphenyl; or apharmaceutically acceptable salt or enantiomer thereof.
 7. A compound offormula (IB) according to claim 1,

wherein R¹ is hydrogen or halogen; R² is hydrogen or halogen; R³ ishydrogen or halogen; R⁴ is C₁₋₆alkyl; R⁵ is hydrogen; R⁶ is hydrogen orcarboxymethyl; Y is —CH₂— or —O—; W is —CH₂—, —C(C₁₋₆alkyl)₂- or —O—; nis 0 or 1; or a pharmaceutically acceptable salt, or enantiomer thereof.8. A compound according to claim 1, wherein R¹ is hydrogen, chloro orbromo; R² is hydrogen or fluoro; R³ is hydrogen or fluoro; R⁴ is methylor ethyl; R⁵ is hydrogen; R⁶ is hydrogen or carboxymethyl; Y is —CH₂— or—O—; W is —CH₂—, —C(CH₃)₂— or —O—; and n is 0 or 1; or apharmaceutically acceptable salt or enantiomer thereof.
 9. A compound offormula (ID) according to claim 1,

wherein R¹ is halogen or C₁₋₆alkyl; R² is hydrogen or halogen; R³ ishydrogen or halogen; R⁴ is C₁₋₆alkyl; R⁵ is hydrogen or carboxy; R⁶ ishydrogen or C₁₋₆alkoxycarbonyl; X is carbonyl; Y is —O— or —N(R⁷)—,wherein R⁷ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,—C_(m)H_(2m)—COOH—C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH, hydroxy-C_(m)H_(2m)—,carboxyspiro[3.3]heptyl or carboxyphenyl-C_(t)H_(2t)—; m is 1-6; and tis 0-6; or a pharmaceutically acceptable salt, or enantiomer thereof.10. A compound according to claim 1, wherein R¹ is chloro, bromo ormethyl; R² is hydrogen or fluoro; R³ is hydrogen or fluoro; R⁴ is methylor ethyl; R⁵ is hydrogen or carboxy; R⁶ is hydrogen ormethyl-O-carbonyl; X is carbonyl; Y is —O—, —N(R⁷)—, wherein R⁷ ishydrogen, methyl, isopropyl, t-butyl, cyclopropyl,carboxy(gemdimethyl)ethyl, carboxy(methyl)ethyl,carboxycyclopropylmethyl, carboxyphenyl, carboxycyclopentyl,carboxycyclohexyl, carboxy(gemdimethyl)propyl,carboxy(gemdimethyl)butyl, carboxycyclobutylmethyl,carboxyspiro[3.3]heptyl, hydroxyethyl or carboxyphenylmethyl; or apharmaceutically acceptable salt or enantiomer thereof.
 11. A compoundof formula (IE) according to claim 1,

wherein R¹ is halogen or C₁₋₆alkyl; R² is hydrogen or halogen; R³ ishydrogen or halogen; R⁴ is C₁₋₆alkyl; R⁵ is hydrogen or carboxy; R⁶ ishydrogen or carboxy-C_(m)H_(2m)—; Y is —O— or —N(R⁷)—, wherein R⁷ isC₁₋₆alkyl, C₃₋₇cycloalkyl, —C_(m)H_(2m)—COOH,—C₃₋₇cycloalkyl-C_(m)H_(2m)—COOH, —C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH,—(C₁₋₆alkoxy)C₁₋₆alkyl-COOH, —C₁₋₆alkyl-O—C₁₋₆alkyl-COOH,carboxyspiro[3.3]heptyl or carboxyphenyl-C_(m)H_(2m)—; W is —CH₂— or—C(C₁₋₆alkyl)₂-; and m is 0-6; or a pharmaceutically acceptable salt, orenantiomer thereof.
 12. A compound according to claim 1, wherein R¹ ischloro or methyl; R² is hydrogen or fluoro; R³ is hydrogen or fluoro; R⁴is methyl or ethyl; R⁵ is hydrogen or carboxy; R⁶ is hydrogen orcarboxymethyl; Y is —O— or —N(R⁷)—, wherein R⁷ is isopropyl, methyl,t-butyl, cyclopropyl, carboxyethyl, carboxypropyl, carboxybutyl,carboxy(gemdimethyl)methyl, carboxy(gemdimethyl)ethyl,carboxy(methyl)ethyl, carboxycyclobutyl, carboxycyclopropylmethyl,carboxycyclopentyl, carboxycyclohexyl, carboxymethylcyclopropyl,carboxy(gemdimethyl)propyl, carboxy(ethyl)ethyl, carboxy(methoxy)ethyl,carboxycyclobutylmethyl, carboxyspiro[3.3]heptyl, carboxymethoxyethyl,carboxymethoxypropyl, carboxyphenylmethyl or carboxyphenyl; W is —CH₂—or —C(CH₃)₂—; or a pharmaceutically acceptable salt, or enantiomerthereof.
 13. A compound of formula (IE) according to claim 1,

wherein R¹ is halogen or C₁₋₆alkyl; R² is hydrogen or halogen; R³ ishydrogen or halogen; R⁴ is C₁₋₆alkyl; R⁵ is hydrogen or carboxy; R⁶ ishydrogen or carboxy-C_(m)H_(2m)—; Y is —N(R⁷)—, wherein R⁷ is hydrogen,C₁₋₆alkyl, C₃₋₇cycloalkyl, —C_(m)H_(2m)—COOH,—C_(m)H_(2m)—C₃₋₇cycloalkyl-COOH or carboxyphenyl; and m is 1-6; or apharmaceutically acceptable salt, or enantiomer thereof.
 14. A compoundaccording to claim 1, wherein R¹ is chloro or methyl; R² is hydrogen orfluoro; R³ is hydrogen or fluoro; R⁴ is methyl or ethyl; R⁵ is hydrogenor carboxy; R⁶ is hydrogen or carboxymethyl; and Y is —N(R⁷)—, whereinR⁷ is hydrogen, methyl, t-butyl, cyclopropyl, carboxy(gemdimethyl)ethyl,carboxy(gemdimethyl)propyl, carboxy(methyl)ethyl,carboxycyclopropylmethyl, carboxycyclobutylmethyl or carboxyphenyl; or apharmaceutically acceptable salt or enantiomer thereof.
 15. A compoundthat is3-[(8aS)-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoicacid, or a pharmaceutically acceptable salt thereof.
 16. A compound thatis hexahydro-1-thia-2,5,7a-triaza-indene 1,1-dioxide, or apharmaceutically acceptable salt thereof.
 17. A compound that is methyl3-oxo-1,2,5,6,7,8-hexahydroimidazo[1,5-a]pyrazine-8a-carboxylate, or apharmaceutically acceptable salt thereof.
 18. A process for thepreparation of a compound of claim 1, or a pharmaceutically acceptablesalt thereof, comprising the reaction of: (a) a compound of formula (A)

with

in the presence of a base.
 19. A pharmaceutical composition comprising acompound according to claim 1, or a pharmaceutically acceptable saltthereof, and a therapeutically inert carrier.
 20. A compound of claim 1,or a pharmaceutically acceptable salt thereof, when manufacturedaccording to a process of claim
 18. 21. A method for the treatment orprophylaxis of hepatitis B virus infection, which method comprisesadministering an effective amount of a compound according to claim 1, ora pharmaceutically acceptable salt thereof.